Heterocyclic compounds and uses thereof

ABSTRACT

Provided herein are heterocyclic compounds of Formula (I), pharmaceutical compositions containing such a compound and their therapeutic uses, methods for their preparation, intermediate compounds, pharmaceutical compositions containing such a compound, and their therapeutic uses.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. §119(e) to U.S.Provisional Application Ser. No. 62/221,508 filed on Sep. 21, 2015,which is hereby incorporated by reference in its entirety

BACKGROUND

The present disclosure relates to bromodomain proteins and compoundswhich modulate bromodomains, and uses therefor. Particular embodimentscontemplate disease indications which are amenable to treatment bymodulation of bromodomains by the compounds of the present disclosure.

SUMMARY

The present disclosure describes a select group of compounds that havedemonstrated superior pharmacokinetics (PK) in comparison to compoundsin earlier studies. More specifically, the compounds of Formula I and IIdisclosed herein are a selection invention of WO 2014/145051. Thecompounds of Formula I and II disclosed herein are novel compounds thatare structurally unique from the specific compounds disclosed in WO2014/145051 because the compounds in this disclosure have adi(pyridin-2-yl)methylene moiety that requires a R¹ substituent asdefined in this disclosure. In contrast, the specific compoundsdisclosed in WO 2014/145051 that have a di(pyridin-2-yl)methylene moietyhave a hydrogen at what would be the R¹ substituent as defined in thisdisclosure. As exemplified in this disclosure, the novel compoundsdescribed herein have demonstrated surprisingly much better PKproperties compared to a structurally similar compound disclosed in WO2014/145051, wherein the only structural difference is that the compounddisclosed in WO 2014/145051 does not have the R¹ substituent as definedin this disclosure.

The present disclosure provides a compound of Formula (I):

or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer,or a deuterated analog thereof, wherein:

R¹ is cyano, halo, or (C₁-C₃)alkyl optionally substituted with 1 to 3substituents independently selected from the group consisting of halo,methyl, ethyl, methoxy and ethoxy; and

X, when present, is halo.

Another embodiment of this disclosure relates to a pharmaceuticalcomposition comprising the compound of Formula (I) and a pharmaceuticalacceptable excipient or carrier.

Another embodiment of this disclosure relates to a pharmaceuticalcomposition comprising the compound of Formula (I) and a pharmaceuticalacceptable excipient or carrier, and another therapeutic agent.

Another embodiment relates to a method for modulating bromodomain, saidmethod comprising: administering to a subject a compound of Formula (I)or a pharmaceutical composition comprising the compound of Formula (I)and a pharmaceutical acceptable excipient or carrier.

Another embodiment relates to a method for treating a subject sufferingor at risk of a disease or condition mediated by a bromodomain, saidmethod comprising administering to the subject in need thereof aneffective amount of a compound of Formula (I) or a pharmaceuticalcomposition comprising the compound of Formula (I) and a pharmaceuticalacceptable excipient or carrier.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts tumor volume over time measurements results as describedin Example 5. The tumor volume over time measurements shown by the topline represents the vehicle. The tumor volume over time measurementsshown by the bottom line represents Compound P-001 10 mg/kg. The tumorvolume over time measurements shown by the middle line representsCompound Z 10 mg/kg.

FIG. 2 illustrates the observed toxicity when dosing Compound P-001 andCompound Z at 10 mg/kg to nu/nu mice over a period of 7 days. The DeltaBody Weight measurement over time measurement shown by the bottom linerepresents Compound Z. The Delta Body Weight measurement over timemeasurement shown by the top line represents Compound P-001.

DETAILED DESCRIPTION I. Definitions

As used herein, the following definitions apply unless clearly indicatedotherwise:

It is noted here that as used in this specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referenceunless the context clearly dictates otherwise.

“Standard Error” as used herein is sample standard deviation divided bythe square root of the sample size.

“Halogen” or “halo” means all halogens, that is, chloro (Cl), fluoro(F), bromo (Br), or iodo (I).

“Cyano” refers to the group —CN.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain hydrocarbon,having the number of carbon atoms designated (i.e. C₁₋₆ means one to sixcarbons). Representative alkyl groups include straight and branchedchain alkyl groups having 1, 2, 3, 4, 5 or 6, carbon atoms. Furtherrepresentative alkyl groups include straight and branched chain alkylgroups having 1, 2 or 3 carbon atoms.

“Optional” or “Optionally” as used throughout the specification meansthat the subsequently described event or circumstance may or may notoccur, and that the description includes instances where the event orcircumstance occurs and instances in which it does not. For example, thephrase “the aromatic group is optionally substituted with one or twoalkyl substituents” means that the alkyl may but need not be present,and the description includes situations where the aromatic group issubstituted with an alkyl group and situations where the aromatic groupis not substituted with the alkyl group.

As used herein in connection with compounds of the present disclosure,the term “synthesizing” and like terms means chemical synthesis from oneor more precursor materials.

“Protecting group” refers to a grouping of atoms that, when attached toa reactive group in a molecule, masks, reduces or prevents thatreactivity. Examples of protecting groups can be found in T. W. Greeneand P. G. Wuts, PROTECTIVE GROUPS IN ORGANIC CHEMISTRY, (Wiley, 4th ed.2006), Beaucage and Iyer, Tetrahedron 48:2223-2311 (1992), and Harrisonand Harrison et al., COMPENDIUM OF SYNTHETIC ORGANIC METHODS, Vols. 1-8(John Wiley and Sons. 1971-1996). Representative amino protecting groupsinclude formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl(CBZ), tert-butoxycarbonyl (Boc), trimethyl silyl (TMS),2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted tritylgroups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC),nitro-veratryloxycarbonyl (NVOC), tri-isopropylsilyl (TIPS),phenylsulphonyl and the like (see also, Boyle, A. L. (Editor),carbamates, amides, N-sulfonyl derivatives, groups of formula —C(O)OR,wherein R is, for example, methyl, ethyl, t-butyl, benzyl, phenylethyl,CH₂═CHCH₂—, and the like, groups of the formula —C(O)R′, wherein R′ is,for example, methyl, phenyl, trifluoromethyl, and the like, groups ofthe formula —SO₂R″, wherein R″ is, for example, tolyl, phenyl,trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl,2,3,6-trimethyl-4-methoxyphenyl, and the like, and silanyl containinggroups, such as 2-trimethylsilylethoxymethyl, t-butyldimethylsilyl,triisopropylsilyl, and the like, CURRENT PROTOCOLS IN NUCLEIC ACIDCHEMISTRY, John Wiley and Sons, New York, Volume 1, 2000).

“Prodrug” means any compound which releases an active parent drugaccording to Formula (I) in vivo when such prodrug is administered to amammalian subject. Prodrugs of a compound of Formula (I) are prepared bymodifying functional groups present in the compound of Formula (I) insuch a way that the modifications may be cleaved in vivo to release theparent compound. Prodrugs may be prepared by modifying functional groupspresent in the compounds in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompounds. Prodrugs include compounds of Formula (I) wherein a hydroxy,amino, carboxyl or sulfhydryl group in a compound of Formula (I) isbonded to any group that may be cleaved in vivo to regenerate the freehydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugsinclude, but are not limited to esters (e.g., acetate, formate, andbenzoate derivatives), amides, guanidines, carbamates (e.g.,N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds ofFormula (I), and the like. Preparation, selection, and use of prodrugsis discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel DeliverySystems,” Vol. 14 of the A.C.S. Symposium Series; “Design of Prodrugs”,ed. H. Bundgaard, Elsevier, 1985; and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, each of which are hereby incorporated by referencein their entirety.

“Tautomer” means compounds produced by the phenomenon wherein a protonof one atom of a molecule shifts to another atom. See, Jerry March,Advanced Organic Chemistry: Reactions, Mechanisms and Structures, FourthEdition, John Wiley & Sons, pages 69-74 (1992). The tautomers also referto one of two or more structural isomers that exist in equilibrium andare readily converted from one isomeric form to another. Examples ofinclude keto-enol tautomers, such as acetone/propen-2-ol, imine-enaminetautomers and the like, ring-chain tautomers, such asglucose/2,3,4,5,6-pentahydroxy-hexanal and the like, the tautomericforms of heteroaryl groups containing a —N═C(H)—NH— ring atomarrangement, such as pyrazoles, imidazoles, benzimidazoles, triazoles,and tetrazoles. Where the compound contains, for example, a keto oroxime group or an aromatic moiety, tautomeric isomerism (tautomerism′)can occur. The compounds described herein may have one or more tautomersand therefore include various isomers. A person of ordinary skill in theart would recognize that other tautomeric ring atom arrangements arepossible. All such isomeric forms of these compounds are expresslyincluded in the present disclosure.

“Isomers” mean compounds having identical molecular formulae but differin the nature or sequence of bonding of their atoms or in thearrangement of their atoms in space. Isomers that differ in thearrangement of their atoms in space are termed “stereoisomers.”“Stereoisomer” and “stereoisomers” refer to compounds that exist indifferent stereoisomeric forms if they possess one or more asymmetriccenters or a double bond with asymmetric substitution and, therefore,can be produced as individual stereoisomers or as mixtures.Stereoisomers include enantiomers and diastereomers. Stereoisomers thatare not mirror images of one another are termed “diastereomers” andthose that are non-superimposable mirror images of each other are termed“enantiomers.” When a compound has an asymmetric center, for example, itis bonded to four different groups, a pair of enantiomers is possible.An enantiomer can be characterized by the absolute configuration of itsasymmetric center and is described by the R- and S-sequencing rules ofCahn and Prelog, or by the manner in which the molecule rotates theplane of polarized light and designated as dextrorotatory orlevorotatory (i.e., as (+) or (−)-isomers respectively). A chiralcompound can exist as either individual enantiomer or as a mixturethereof. A mixture containing equal proportions of the enantiomers iscalled a “racemic mixture”. Unless otherwise indicated, the descriptionis intended to include individual stereoisomers as well as mixtures. Themethods for the determination of stereochemistry and the separation ofstereoisomers are well-known in the art (see discussion in Chapter 4 ofADVANCED ORGANIC CHEMISTRY, 6th edition J. March, John Wiley and Sons,New York, 2007). Certain molecules claimed herein can exist in differentenantiomeric and diastereomeric forms.

The compounds of the present disclosure may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabelled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I), carbon-14 (¹⁴C), carbon-11 (¹¹C) or fluorine-18(¹⁸F). All isotopic variations of the compounds of the presentdisclosure, whether radioactive or not, are intended to be encompassedwithin the scope of the present disclosure.

Certain molecules claimed in this patent can have one or more hydrogenatoms of the molecules replaced by one or more deuterium atoms includingperdeuterated analogs, all such variants of these compounds are claimed.Further, it should be noted that the term “deuterated analog” refers tocompounds where at least one hydrogen atom has been replaced by adeuterium atom. The term “deuterated” as used herein alone or as part ofa group, means substituted deuterium atoms. When a particular positionis designated as holding deuterium (stated as “D” or “deuterium”), it isunderstood that the abundance of deuterium at that position issubstantially greater than the natural abundance of deuterium, which is0.015% (i.e., at least 50.1% incorporation of deuterium).

The deuterated analog of the present disclosure may be a fully orpartially deuterium substituted derivative. The deuterium substitutedcompound of the present disclosure can hold a fully or partiallydeuterium substituted alkyl, aryl or heteroaryl group. In oneembodiment, the deuterium substituted compound of the present disclosureholds a fully or partially deuterium substituted alkyl group, e.g.,—CD₃, CD₂CD₃, —CD₂CD₂CD₃ and the like. In another embodiment, thedeuterium substituted compound of the present disclosure holds a fullyor partially deuterium substituted aryl, such as phenyl, e.g., C₆D₅ or afully or partially deuterium substituted heteroaryl, e.g., pyridyl-d₃,and the like.

The disclosure also embraces isotopically-labeled compounds of thepresent disclosure which are identical to those recited herein, but forthe fact that one or more atoms are replaced by an atom having an atomicmass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the present disclosure include isotopes of hydrogen,carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as,but not limited to ²H (deuterium D), ³H (tritium), ¹¹C, ¹³C, ¹⁴C, ¹⁵N,¹⁸F, ³¹F, ³²F, ³⁵S, ³⁶Cl, and Unless otherwise stated, when a positionis designated specifically as “H” or “hydrogen,” the position isunderstood to have hydrogen at its natural abundance isotopiccomposition or its isotopes, such as deuterium (D) or tritium (³H).Certain isotopically-labeled compounds of the present disclosure (e.g.,those labeled with ³H and ¹⁴C) are useful in compound and/or substratetissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e.,¹⁴C) and fluorine-18 (¹⁸F) isotopes are useful for their ease ofpreparation and detectability. Further, substitution with heavierisotopes such as deuterium (i.e., ²H) may afford certain therapeuticadvantages resulting from greater metabolic stability (e.g., increasedin vivo half-life or reduced dosage requirements) and hence may bepreferred in some circumstances. Isotopically labeled compounds of thepresent disclosure can generally be prepared by following proceduresanalogous to those disclosed in the Schemes and in the Examples hereinbelow, by substituting an isotopically labeled reagent for anon-isotopically labeled reagent.

Certain compounds of the present disclosure can exist in unsolvatedforms as well as solvated forms, including hydrated forms. “Hydrate”refers to a complex formed by combination of water molecules withmolecules or ions of the solute. “Solvate” refers to a complex formed bycombination of solvent molecules with molecules or ions of the solute.The solvent can be an organic compound, an inorganic compound, or amixture of both. Solvate is meant to include hydrate. Some examples ofsolvents include, but are not limited to, methanol,N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water. Ingeneral, the solvated forms are equivalent to unsolvated forms and areencompassed within the scope of the present disclosure. Certaincompounds of the present disclosure may exist in multiple crystalline oramorphous forms. In general, all physical forms are equivalent for theuses contemplated by the present disclosure and are intended to bewithin the scope of the present disclosure.

“Solid form” refers to a solid preparation (i.e. a preparation that isneither gas nor liquid) of a pharmaceutically active compound that issuitable for administration to an intended animal subject fortherapeutic purposes. The solid form includes any complex, such as asalt, co-crystal or an amorphous complex, as well as any polymorph ofthe compound. The solid form may be substantially crystalline,semi-crystalline or substantially amorphous. The solid form may beadministered directly or used in the preparation of a suitablecomposition having improved pharmaceutical properties. For example, thesolid form may be used in a formulation comprising at least onepharmaceutically acceptable carrier or excipient.

The term “pharmaceutically acceptable” indicates that the indicatedmaterial does not have properties that would cause a reasonably prudentmedical practitioner to avoid administration of the material to apatient, taking into consideration the disease or conditions to betreated and the respective route of administration. For example, it iscommonly required that such a material be essentially sterile, e.g., forinjectables.

“Pharmaceutically acceptable salt” refers to a salt which is acceptablefor administration to a patient, such as a mammal (e.g., salts havingacceptable mammalian safety for a given dosage regime). Such salts canbe derived from pharmaceutically acceptable inorganic or organic basesand from pharmaceutically-acceptable inorganic or organic acids,depending on the particular substituents found on the compoundsdescribed herein. When compounds of the present disclosure containrelatively acidic functionalities, base addition salts can be obtainedby contacting the neutral form of such compounds with a sufficientamount of the desired base, either neat or in a suitable inert solvent.Salts derived from pharmaceutically acceptable inorganic bases includealuminum, ammonium, calcium, copper, ferric, ferrous, lithium,magnesium, manganic, manganous, potassium, sodium, zinc and the like.Salts derived from pharmaceutically acceptable organic bases includesalts of primary, secondary, tertiary and quaternary amines, includingsubstituted amines, cyclic amines, naturally-occurring amines and thelike, such as arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine,tromethamine, N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, meglumine (N-methyl-glucamine) and the like. Whencompounds of the present disclosure contain relatively basicfunctionalities, acid addition salts can be obtained by contacting theneutral form of such compounds with a sufficient amount of the desiredacid, either neat or in a suitable inert solvent. Salts derived frompharmaceutically acceptable acids include acetic, trifluoroacetic,propionic, ascorbic, benzenesulfonic, benzoic, camphosulfonic, citric,ethanesulfonic, fumaric, glycolic, gluconic, glucoronic, glutamic,hippuric, hydrobromic, hydrochloric, isethionic, lactic, lactobionic,maleic, malic, mandelic, methanesulfonic, mucic, naphthalenesulfonic,nicotinic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric,hydroiodic, carbonic, tartaric, p-toluenesulfonic, pyruvic, aspartic,benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic,phenylacetic, embonic (pamoic), ethanesulfonic, benzenesulfonic,2-hydroxyethanesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic,algenic, hydroxybutyric, galactaric and galacturonic acid and the like.

Also included are salts of amino acids such as arginate and the like,and salts of organic acids like glucuronic or galactunoric acids and thelike (see, for example, Berge, S. M. et al, “Pharmaceutical Salts,” J.Pharmaceutical Science, 1977, 66:1-19). Certain specific compounds ofthe present disclosure contain both basic and acidic functionalitiesthat allow the compounds to be converted into either base or acidaddition salts.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present disclosure.

As used herein, the term “composition” refers to a formulation suitablefor administration to an intended animal subject for therapeuticpurposes that contains at least one pharmaceutically active compound andat least one pharmaceutically acceptable carrier or excipient.

“Unit dosage form” refers to a composition intended for a singleadministration to treat a subject suffering from a disease or medicalcondition. Each unit dosage form typically comprises each of the activeingredients of this disclosure plus pharmaceutically acceptableexcipients. Examples of unit dosage forms are individual tablets,individual capsules, bulk powders, liquid solutions, ointments, creams,eye drops, suppositories, emulsions or suspensions. Treatment of thedisease or condition may require periodic administration of unit dosageforms, for example: one unit dosage form two or more times a day, onewith each meal, one every four hours or other interval, or only one perday. The expression “oral unit dosage form” indicates a unit dosage formdesigned to be taken orally.

In the present context, the term “therapeutically effective” or“effective amount” indicates that a compound or amount of the compoundwhen administered is sufficient or effective to prevent, alleviate, orameliorate one or more symptoms of a disease, disorder or medicalcondition being treated, and/or to prolong the survival of the subjectbeing treated. The therapeutically effective amount will vary dependingon the compound, the disease, disorder or condition and its severity andthe age, weight, etc., of the mammal to be treated. In general,satisfactory results in subjects are indicated to be obtained at a dailydosage of from about 0.1 to about 10 g/kg subject body weight. In someembodiments, a daily dose ranges from about 0.10 to 10.0 mg/kg of bodyweight, from about 1.0 to 3.0 mg/kg of body weight, from about 3 to 10mg/kg of body weight, from about 3 to 150 mg/kg of body weight, fromabout 3 to 100 mg/kg of body weight, from about 10 to 100 mg/kg of bodyweight, from about 10 to 150 mg/kg of body weight, or from about 150 to1000 mg/kg of body weight. The dosage can be conveniently administered,e.g., in divided doses up to four times a day or in sustained-releaseform.

Bromodomains are a family of (˜110 amino acid) structurally andevolutionary conserved protein interaction modules that specificallyrecognize acetylated lysines present in substrate proteins, notablyhistones. Bromodomains exist as components of large multidomain nuclearproteins that are associated with chromatin remodeling, cell signalingand transcriptional control. There are a total of 61 human bromodomainsfound within 46 human proteins. Examples of bromodomain-containingproteins with known functions include: (i) histone acetyltransferases(HATs), including CREBBP, GCNS, PCAF and TAFII250; (ii)methyltransferases such as ASH1L and MLL; (iii) components ofchromatin-remodeling complexes such as Swi2/Snf2; and (iv) a number oftranscriptional regulators (Florence et al. Front. Biosci. 2001, 6,D1008-1018).

As used herein, the terms “bromodomain mediated,” “BET-mediated,”“BRD2-mediated,” “BRD3-mediated,” “BRD4-mediated,” and/or“BRDT-mediated” disorders or conditions means any disease or otherdeleterious condition in which one or more of the bromodomain-containingproteins, such as BET proteins, such as BRD2, BRD3, BRD4 and/or BRDT, ora mutant thereof, are known to play a role. Accordingly, anotherembodiment of the present disclosure relates to treating or lesseningthe severity of one or more diseases in which one or more of thebromodomain-containing proteins, such as BET proteins, such as BRD2,BRD3, BRD4, and/or BRDT, or a mutant thereof, are known to play a role.For example, a disease or condition in which the biological function ofbromodomain affects the development and/or course of the disease orcondition, and/or in which modulation of bromodomain alters thedevelopment, course, and/or symptoms. Bromodomain mediated disease orcondition includes a disease or condition for which bromodomaininhibition provides a therapeutic benefit, e.g. wherein treatment withbromodomain inhibitors, including compounds described herein, provides atherapeutic benefit to the subject suffering from or at risk of thedisease or condition. The term “inhibiting bromodomain” or “bromodomaininhibitor” means a compound which inhibits the binding of a bromodomainwith its cognate acetylated proteins, for example, the bromodomaininhibitor is a compound which inhibits the binding of a bromodomain toacetylated lysine residues.

In the present context, the terms “synergistically effective” or“synergistic effect” indicate that two or more compounds that aretherapeutically effective, when used in combination, provide improvedtherapeutic effects greater than the additive effect that would beexpected based on the effect of each compound used by itself.

By “assaying” is meant the creation of experimental conditions and thegathering of data regarding a particular result of the exposure tospecific experimental conditions. For example, enzymes can be assayedbased on their ability to act upon a detectable substrate. A compoundcan be assayed based on its ability to bind to a particular targetmolecule or molecules.

As used herein, the terms “ligand” and “modulator” are used equivalentlyto refer to a compound that changes (i.e., increases or decreases) theactivity of a target biomolecule, e.g., an protein such as abromodomain. Generally a ligand or modulator will be a small molecule,where “small molecule refers to a compound with a molecular weight of1500 Daltons or less, or preferably 1000 Daltons or less, 800 Daltons orless, or 600 Daltons or less. Thus, an “improved ligand” is one thatpossesses better pharmacological and/or pharmacokinetic properties thana reference compound, where “better” can be defined by one skilled inthe relevant art for a particular biological system or therapeutic use.

The term “binds” in connection with the interaction between a target anda potential binding compound indicates that the potential bindingcompound associates with the target to a statistically significantdegree as compared to association with proteins generally (i.e.,non-specific binding). Thus, the term “binding compound” refers to acompound that has a statistically significant association with a targetmolecule. Preferably a binding compound interacts with a specifiedtarget with a dissociation constant (K_(D)) of 1 mM or less, 1 μM orless, 100 nM or less, 10 nM or less, or 1 nM or less.

As used herein, the term “modulating” or “modulate” refers to an effectof altering a biological activity, especially a biological activityassociated with a particular biomolecule such as a bromodomain protein.For example, an agonist or antagonist of a particular biomoleculemodulates the activity of that biomolecule, e.g., an enzyme, by eitherincreasing (e.g. agonist, activator), or decreasing (e.g. antagonist,inhibitor) the activity of the biomolecule, such as an enzyme. Suchactivity is typically indicated in terms of an inhibitory concentration(IC₅₀) or excitation concentration (EC₅₀) of the compound for aninhibitor or activator, respectively, with respect to, for example, anenzyme.

In the context of the use, testing, or screening of compounds that areor may be modulators, the term “contacting” means that the compound(s)are caused to be in sufficient proximity to a particular molecule,complex, cell, tissue, organism, or other specified material thatpotential binding interactions and/or chemical reaction between thecompound and other specified material can occur.

As used herein, the term “subject” refers to a living organism that istreated with compounds as described herein, including, but not limitedto, any mammal, such as a human, other primates, sports animals, animalsof commercial interest such as cattle, farm animals such as horses, orpets such as dogs and cats.

The term “administering” refers to oral administration, administrationas a suppository, topical contact, intravenous, intraperitoneal,intramuscular, intralesional, intranasal or subcutaneous administration,or the implantation of a slow-release device e.g., a mini-osmotic pump,to a subject. Administration is by any route, including parenteral andtransmucosal (e.g., buccal, sublingual, palatal, gingival, nasal,vaginal, rectal, or transdermal). Parenteral administration includes,e.g., intravenous, intramuscular, intra-arteriole, intradermal,subcutaneous, intraperitoneal, intraventricular, and intracranial. Othermodes of delivery include, but are not limited to, the use of liposomalformulations, intravenous infusion, transdermal patches, etc.

The terms “prevent,” “preventing,” “prevention” and grammaticalvariations thereof as used herein, refers to a method of partially orcompletely delaying or precluding the onset or recurrence of a disease,disorder or condition and/or one or more of its attendant symptoms orbarring a subject from acquiring or reacquiring a disorder or conditionor reducing a subject's risk of acquiring or reacquiring a disorder orcondition or one or more of its attendant symptoms.

In connection with amino acid or nucleic sequences, the term “purified”indicates that the subject molecule constitutes a significantly greaterproportion of the biomolecules in a composition than the proportionobserved in a prior composition, e.g., in a cell culture. The greaterproportion can be 2-fold, 5-fold, 10-fold, or more than 10-fold, withrespect to the proportion found in the prior composition.

In addition, abbreviations as used herein have respective meanings asfollows:

° C. Degree Celsius % F Bioavailability (%) AUC Area under the curve BOCtert-Butoxycarbonyl BSA Bovine serum albumin CL Apparent total bodyclearance of the drug from plasma C_(max) Maximum plasma concentrationDMAP 4-dimethylaminopyridine DMSO Dimethylsulfoxide DTT DithiothreitolEtOAc Ethyl acetate Et₂O Diethyl ether FBS Fetal bovine serum g GramHEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid HPLC Highperformance liquid chromatography hr(s) Hour(s) Kg or Kg Kilogram LLiter LC-MS Liquid chromatography-mass spectrometry LC/MS/MS Liquidchromatography-tandem mass spectrometry M Molar MeOH Methanol MS (ESI)Mass spectrometry electrospray ionization mg Milligram min Minutes mL orml Milliliter mm Millimeter mM Millimolar mmol Millimole mol Mole MTDMaximum tolerated dose N Normal nm nanometers nM Nanomolar PDpharmacodynamics po By mouth QD Once daily T_(1/2) Half-life T_(max)Peak time THF Tetrahydrofuran V_(ss) Apparent volume of distribution atsteady state μg Microgram μL Microliter μM Micromolar

II. General

The present disclosure concerns compounds of Formula (I), (II), and allsub-generic formulae, compounds as recited in the claims, and compoundsdescribed herein that are modulators of bromodomains and the use of suchcompounds in the treatment of diseases or conditions. Also disclosedherein are compounds useful for the synthesis of compounds of Formula(I) and (II).

III. Compounds

In some embodiments, the present disclosure provides compounds ofFormula (I) and all sub-generic formulae and compounds disclosed herein,or a pharmaceutically acceptable salt, hydrate, solvate, tautomer orisomer thereof.

In one embodiment, the present disclosure provides a compound of Formula(I):

or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer,or a deuterated analog thereof, wherein:

R¹ is cyano, halo, or (C₁-C₃)alkyl optionally substituted with 1 to 3substituents independently selected from the group consisting of halo,methyl, ethyl, methoxy and ethoxy; and

X, when present, is halo.

In another embodiment of Formula (I), R¹ is (C₁-C₂)alkyl, cyano orfluoro.

In another embodiment of Formula (I), R¹ is methyl, cyano or fluoro.

In another embodiment of Formula (I), R¹ is (C₁-C₂)alkyl. In anotherembodiment of Formula (I), R¹ is methyl. In another embodiment ofFormula (I), R¹ is cyano. In another embodiment of Formula (I), R¹ ishalo. In another embodiment of Formula (I), R¹ is fluoro.

In another embodiment of Formula (I), R¹ is (C₁-C₂)alkyl optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of halo, methyl, ethyl, methoxy and ethoxy. In anotherembodiment of Formula (I), R¹ is methyl optionally substituted with 1 to3 substituents independently selected from the group consisting of halo,methyl, ethyl, methoxy and ethoxy.

In another embodiment of Formula (I), X is absent. In another embodimentof Formula (I), X is halo. In another embodiment of Formula (I), X isfluoro. In another embodiment of Formula (I), X is chloro.

In another embodiment of Formula (I), R¹ is (C₁-C₃)alkyl, and X isabsent. In another embodiment of Formula (I), R¹ is (C₁-C₃)alkyl, and Xis halo. In another embodiment of Formula (I), R¹ is (C₁-C₃)alkyl and Xis fluoro. In another embodiment of Formula (I), R¹ is (C₁-C₃)alkyl andX is chloro. In another embodiment of Formula (I), R¹ is (C₁-C₂)alkyland X is absent. In another embodiment of Formula (I), R¹ is(C₁-C₂)alkyl and X is halo. In another embodiment of Formula (I), R¹ is(C₁-C₂)alkyl and X is fluoro. In another embodiment of Formula (I), R¹is (C₁-C₂)alkyl and X is chloro.

In another embodiment of Formula (I), R¹ is (C₁-C₃)alkyl optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of halo, methyl, ethyl, methoxy and ethoxy, and X isabsent. In another embodiment of Formula (I), R¹ is (C₁-C₃)alkyloptionally substituted with 1 to 3 substituents independently selectedfrom the group consisting of halo, methyl, ethyl, methoxy and ethoxy,and X is halo. In another embodiment of Formula (I), R¹ is (C₁-C₃)alkyloptionally substituted with 1 to 3 substituents independently selectedfrom the group consisting of halo, methyl, ethyl, methoxy and ethoxy,and X is fluoro. In another embodiment of Formula (I), R¹ is(C₁-C₃)alkyl and X is chloro.

In another embodiment of Formula (I), R¹ is (C₁-C₂)alkyl optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of halo, methyl, ethyl, methoxy and ethoxy, and X isabsent.

In another embodiment of Formula (I), R¹ is (C₁-C₂)alkyl optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of halo, methyl, ethyl, methoxy and ethoxy, and X ishalo. In another embodiment of Formula (I), R¹ is (C₁-C₂)alkyloptionally substituted with 1 to 3 substituents independently selectedfrom the group consisting of halo, methyl, ethyl, methoxy and ethoxy,and X is fluoro. In another embodiment of Formula (I), R¹ is(C₁-C₂)alkyl optionally substituted with 1 to 3 substituentsindependently selected from the group consisting of halo, methyl, ethyl,methoxy and ethoxy, and X is chloro.

In another embodiment of Formula (I), R¹ is methyl and X is absent. Inanother embodiment of Formula (I), R¹ is methyl and X is halo. Inanother embodiment of Formula (I), R¹ is methyl and X is fluoro. Inanother embodiment of Formula (I), R¹ is methyl and X is chloro.

In another embodiment of Formula (I), R¹ is methyl optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of halo, methyl, ethyl, methoxy and ethoxy, and X isabsent. In another embodiment of Formula (I), R¹ is methyl optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of halo, methyl, ethyl, methoxy and ethoxy, and X ishalo. In another embodiment of Formula (I), R¹ is methyl optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of halo, methyl, ethyl, methoxy and ethoxy, and X isfluoro. In another embodiment of Formula (I), R¹ is methyl optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of halo, methyl, ethyl, methoxy and ethoxy, and X ischloro.

Another embodiment of Formula (I) is the compound of Formula (II):

or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer,or a deuterated analog thereof, wherein:

R¹ is cyano, halo, or (C₁-C₃)alkyl optionally substituted with 1 to 3substituents independently selected from the group consisting of halo,methyl, ethyl, methoxy and ethoxy.

In another embodiment of Formula (II), R¹ is (C₁-C₂)alkyl, cyano orfluoro.

In another embodiment of Formula (II), R¹ is methyl, cyano or fluoro.

In another embodiment of Formula (II), R¹ is cyano, halo, or (C₁-C₂)optionally substituted with one or more halo. In another embodiment ofFormula (II), R¹ is cyano, halo, or methyl optionally substituted withone or more halo. In another embodiment of Formula (II), R¹ is methyl.In another embodiment of Formula (II), R¹ is methyl optionallysubstituted with 1-3 halo. In another embodiment of Formula (II), R¹ ismethyl optionally substituted with 1-3 chloro. In another embodiment ofFormula (II), R¹ is methyl optionally substituted with 1-3 fluoro. Inanother embodiment of Formula (II), R¹ is cyano. Another embodiment ofFormula (II), R¹ is fluoro.

In another embodiment of Formula (II), R¹ is cyano, halo, or (C₁-C₂)optionally substituted with 1 to 3 substituents independently selectedfrom the group consisting of halo, methyl, ethyl, methoxy and ethoxy. Inanother embodiment of Formula (II), R¹ is methyl optionally substitutedwith 1 to 3 substituents independently selected from the groupconsisting of halo, methyl, ethyl, methoxy and ethoxy.

Another embodiment of the compound of Formula I or II is a compound ofTable I or a pharmaceutically acceptable salt, a solvate, a tautomer, anisomer, or a deuterated analog of any of the compounds in Table I:

TABLE I Number Structure Name [M + H⁺]⁺ P-001

4-(1-(1,1-di(pyridin-2-yl)ethyl)-6- (3,5-dimethoxylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)benzoic acid 515.56 P-004

4-(6-(3,5-dimethylisoxazol-4-yl)-1- (fluorodi(pyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)benzoic acid 519.52 P-006

4-(1-(cyanodi(pyridin-2-yl)methyl)- 6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)benzoic acid 526.45

Another embodiment of this disclosure relates to a compounds that areintermediate compounds useful for the synthesis of the compound ofFormula (I), Formula (II), or of the compounds listed in Table I,wherein the intermediate compound is one of the following Formula:

or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer,or a deuterated analog thereof.Organic Synthetic Techniques

A wide array of organic synthetic techniques exist in the art tofacilitate the construction of potential modulators. Many of theseorganic synthetic methods are described in detail in standard referencesources utilized by those skilled in the art. One example of such areference is March, 1994, Advanced Organic Chemistry; Reactions,Mechanisms and Structure, New York, McGraw Hill. Thus, the techniquesuseful to synthesize a potential modulator of bromodomain function arereadily available to those skilled in the art of organic chemicalsynthesis.

Alternative Compound Forms or Derivatives

Compounds contemplated herein are described with reference to bothgeneric formulae and specific compounds. In addition, compoundsdisclosed herein may exist in a number of different forms orderivatives, all within the scope of the present disclosure. Alternativeforms or derivatives, include, for example, (a) prodrugs, and activemetabolites (b) tautomers, isomers (including stereoisomers andregioisomers), and racemic mixtures (c) pharmaceutically acceptablesalts and (d) solid forms, including different crystal forms,polymorphic or amorphous solids, including hydrates and solvatesthereof, and other forms.

(a) Prodrugs and Metabolites

In addition to the present formulae and compounds described herein, thepresent disclosure also includes prodrugs (generally pharmaceuticallyacceptable prodrugs), active metabolic derivatives (active metabolites),and their pharmaceutically acceptable salts.

Prodrugs are compounds or pharmaceutically acceptable salts thereofwhich, when metabolized under physiological conditions or when convertedby solvolysis, yield the desired active compound. Prodrugs include,without limitation, esters, amides, carbamates, carbonates, ureides,solvates, or hydrates of the active compound. Typically, the prodrug isinactive, or less active than the active compound, but may provide oneor more advantageous handling, administration, and/or metabolicproperties. For example, some prodrugs are esters of the activecompound; during metabolysis, the ester group is cleaved to yield theactive drug. Esters include, for example, esters of a carboxylic acidgroup, or S-acyl or O-acyl derivatives of thiol, alcohol, or phenolgroups. In this context, a common example is an alkyl ester of acarboxylic acid. Prodrugs may also include variants wherein an —NH groupof the compound has undergone acylation, such as the 1-position of the1H-pyrrolo[2,3-b]pyridine ring, or the nitrogen of the sulfonamide groupof compounds as described herein, where cleavage of the acyl groupprovides the free —NH group of the active drug. Some prodrugs areactivated enzymatically to yield the active compound, or a compound mayundergo further chemical reaction to yield the active compound. Prodrugsmay proceed from prodrug form to active form in a single step or mayhave one or more intermediate forms which may themselves have activityor may be inactive.

As described in The Practice of Medicinal Chemistry, Ch. 31-32 (Ed.Wermuth, Academic Press, San Diego, Calif., 2001), prodrugs can beconceptually divided into two non-exclusive categories, bioprecursorprodrugs and carrier prodrugs. Generally, bioprecursor prodrugs arecompounds that are inactive or have low activity compared to thecorresponding active drug compound, that contain one or more protectivegroups and are converted to an active form by metabolism or solvolysis.Both the active drug form and any released metabolic products shouldhave acceptably low toxicity. Typically, the formation of active drugcompound involves a metabolic process or reaction that is one of thefollowing types:

Oxidative reactions: Oxidative reactions are exemplified withoutlimitation by reactions such as oxidation of alcohol, carbonyl, and acidfunctionalities, hydroxylation of aliphatic carbons, hydroxylation ofalicyclic carbon atoms, oxidation of aromatic carbon atoms, oxidation ofcarbon-carbon double bonds, oxidation of nitrogen-containing functionalgroups, oxidation of silicon, phosphorus, arsenic, and sulfur, oxidativeN-dealkylation, oxidative O- and S-dealkylation, oxidative deamination,as well as other oxidative reactions.

Reductive reactions: Reductive reactions are exemplified withoutlimitation by reactions such as reduction of carbonyl functionalities,reduction of alcohol functionalities and carbon-carbon double bonds,reduction of nitrogen-containing functional groups, and other reductionreactions.

Reactions without change in the oxidation state: Reactions withoutchange in the state of oxidation are exemplified without limitation byreactions such as hydrolysis of esters and ethers, hydrolytic cleavageof carbon-nitrogen single bonds, hydrolytic cleavage of non-aromaticheterocycles, hydration and dehydration at multiple bonds, new atomiclinkages resulting from dehydration reactions, hydrolyticdehalogenation, removal of hydrogen halide molecule, and other suchreactions.

Carrier prodrugs are drug compounds that contain a transport moiety,e.g., that improves uptake and/or localized delivery to a site(s) ofaction. Desirably for such a carrier prodrug, the linkage between thedrug moiety and the transport moiety is a covalent bond, the prodrug isinactive or less active than the drug compound, the prodrug and anyrelease transport moiety are acceptably non-toxic. For prodrugs wherethe transport moiety is intended to enhance uptake, typically therelease of the transport moiety should be rapid. In other cases, it isdesirable to utilize a moiety that provides slow release, e.g., certainpolymers or other moieties, such as cyclodextrins. (See, e.g., Cheng etal., U.S. Patent Publ. No. 20040077595, application Ser. No. 10/656,838,incorporated herein by reference.) Such carrier prodrugs are oftenadvantageous for orally administered drugs. In some instances, thetransport moiety provides targeted delivery of the drug, for example thedrug may be conjugated to an antibody or antibody fragment. Carrierprodrugs can, for example, be used to improve one or more of thefollowing properties: increased lipophilicity, increased duration ofpharmacological effects, increased site-specificity, decreased toxicityand adverse reactions, and/or improvement in drug formulation (e.g.,stability, water solubility, suppression of an undesirable organolepticor physiochemical property). For example, lipophilicity can be increasedby esterification of hydroxyl groups with lipophilic carboxylic acids,or of carboxylic acid groups with alcohols, e.g., aliphatic alcohols.Wermuth, supra.

Metabolites, e.g., active metabolites, overlap with prodrugs asdescribed above, e.g., bioprecursor prodrugs. Thus, such metabolites arepharmacologically active compounds or compounds that further metabolizeto pharmacologically active compounds that are derivatives resultingfrom metabolic processes in the body of a subject. Of these, activemetabolites are such pharmacologically active derivative compounds. Forprodrugs, the prodrug compound is generally inactive or of loweractivity than the metabolic product. For active metabolites, the parentcompound may be either an active compound or may be an inactive prodrug.For example, in some compounds, one or more alkoxy groups can bemetabolized to hydroxyl groups while retaining pharmacologic activityand/or carboxyl groups can be esterified, e.g., glucuronidation. In somecases, there can be more than one metabolite, where an intermediatemetabolite(s) is further metabolized to provide an active metabolite.For example, in some cases a derivative compound resulting frommetabolic glucuronidation may be inactive or of low activity, and can befurther metabolized to provide an active metabolite.

Metabolites of a compound may be identified using routine techniquesknown in the art, and their activities determined using tests such asthose described herein. See, e.g., Bertolini et al., 1997, 1 Med. Chem.,40:2011-2016; Shan et al., 1997, J Pharm Sci 86(7):756-757; Bagshawe,1995, Drug Dev. Res., 34:220-230; Wermuth, supra.

(b) Tautomers, Stereoisomers, and Regioisomers

It is understood that some compounds may exhibit tautomerism. In suchcases, the formulae provided herein expressly depict only one of thepossible tautomeric forms. It is therefore to be understood that theformulae provided herein are intended to represent any tautomeric formof the depicted compounds and are not to be limited merely to thespecific tautomeric form depicted by the drawings of the formulae.

Likewise, some of the compounds according to the present disclosure mayexist as stereoisomers, i.e. having the same atomic connectivity ofcovalently bonded atoms yet differing in the spatial orientation of theatoms. For example, compounds may be optical stereoisomers, whichcontain one or more chiral centers, and therefore, may exist in two ormore stereoisomeric forms (e.g. enantiomers or diastereomers). Thus,such compounds may be present as single stereoisomers (i.e., essentiallyfree of other stereoisomers), racemates, and/or mixtures of enantiomersand/or diastereomers. As another example, stereoisomers includegeometric isomers, such as cis- or trans-orientation of substituents onadjacent carbons of a double bond. All such single stereoisomers,racemates and mixtures thereof are intended to be within the scope ofthe present disclosure. Unless specified to the contrary, all suchstereoisomeric forms are included within the formulae provided herein.

In some embodiments, a chiral compound of the present disclosure is in aform that contains at least 80% of a single isomer (60% enantiomericexcess (“e.e.”) or diastereomeric excess (“d.e.”)), or at least 85% (70%e.e. or d.e.), 90% (80% e.e. or d.e.), 95% (90% e.e. or d.e.), 97.5%(95% e.e. or d.e.), or 99% (98% e.e. or d.e.). As generally understoodby those skilled in the art, an optically pure compound having onechiral center is one that consists essentially of one of the twopossible enantiomers (i.e., is enantiomerically pure), and an opticallypure compound having more than one chiral center is one that is bothdiastereomerically pure and enantiomerically pure. In some embodiments,the compound is present in optically pure form, such optically pure formbeing prepared and/or isolated by methods known in the art (e.g. byrecrystallization techniques, chiral synthetic techniques (includingsynthesis from optically pure starting materials), and chromatographicseparation using a chiral column.

(c) Pharmaceutically Acceptable Salts

Unless specified to the contrary, specification of a compound hereinincludes pharmaceutically acceptable salts of such compound. Thus,compounds described herein and recited in any of the claims can be inthe form of pharmaceutically acceptable salts, or can be formulated aspharmaceutically acceptable salts. Contemplated pharmaceuticallyacceptable salt forms include, without limitation, mono, bis, tris,tetrakis, and so on. Pharmaceutically acceptable salts are non-toxic inthe amounts and concentrations at which they are administered. Thepreparation of such salts can facilitate the pharmacological use byaltering the physical characteristics of a compound without preventingit from exerting its physiological effect. Useful alterations inphysical properties include lowering the melting point to facilitatetransmucosal administration and increasing the solubility to facilitateadministering higher concentrations of the drug. A compound of thepresent disclosure may possess a sufficiently acidic, a sufficientlybasic, or both functional groups, and accordingly can react with any ofa number of inorganic or organic bases, and inorganic and organic acids,to form a pharmaceutically acceptable salt.

Pharmaceutically acceptable salts include acid addition salts such asthose containing chloride, bromide, iodide, hydrochloride, acetate,phenylacetate, acrylate, ascorbate, aspartate, benzoate,2-phenoxybenzoate, 2-acetoxybenzoate, dinitrobenzoate, hydroxybenzoate,methoxybenzoate, methylbenzoate, bicarbonate, butyne-1,4 dioate,hexyne-1,6-dioate, caproate, caprylate, chlorobenzoate, cinnamate,citrate, decanoate, formate, fumarate, glycolate, gluconate, glucarate,glucuronate, glucose-6-phosphate, glutamate, heptanoate, hexanoate,isethionate, isobutyrate, gamma-hydroxybutyrate, phenylbutyrate,lactate, malate, maleate, hydroxymaleate, methylmaleate, malonate,mandelate, nicotinate, nitrate, isonicotinate, octanoate, oleate,oxalate, pamoate, phosphate, monohydrogenphosphate, dihydrogenphosphate,orthophosphate, metaphosphate, pyrophosphate, 2-phosphoglycerate,3-phosphoglycerate, phthalate, propionate, phenylpropionate, propiolate,pyruvate, quinate, salicylate, 4-aminosalicylate, sebacate, stearate,suberate, succinate, sulfate, pyrosulfate, bisulfate, sulfite,bisulfate, sulfamate, sulfonate, benzenesulfonate (i.e. besylate),ethanesulfonate (i.e. esylate), ethane-1,2-disulfonate,2-hydroxyethanesulfonate (i.e. isethionate), methanesulfonate (i.e.mesylate), naphthalene-1-sulfonate, naphthalene-2-sulfonate (i.e.napsylate), propanesulfonate, p-toluenesulfonate (i.e. tosylate),xylenesulfonates, cyclohexylsulfamate, tartrate, and trifluoroacetate.These pharmaceutically acceptable acid addition salts can be preparedusing the appropriate corresponding acid.

When acidic functional groups, such as carboxylic acid or phenol arepresent, pharmaceutically acceptable salts also include basic additionsalts such as those containing benzathine, chloroprocaine, choline,ethanolamine, diethanolamine, triethanolamine, t-butylamine,dicyclohexylamine, ethylenediamine, N,N′-dibenzylethylenediamine,meglumine, hydroxyethylpyrrolidine, piperidine, morpholine, piperazine,procaine, aluminum, calcium, copper, iron, lithium, magnesium,manganese, potassium, sodium, zinc, ammonium, and mono-, di-, ortri-alkylamines (e.g. diethylamine), or salts derived from amino acidssuch as L-histidine, L-glycine, L-lysine, and L-arginine. For example,see Remington's Pharmaceutical Sciences, 19^(th) ed., Mack PublishingCo., Easton, Pa., Vol. 2, p. 1457, 1995. These pharmaceuticallyacceptable base addition salts can be prepared using the appropriatecorresponding base.

Pharmaceutically acceptable salts can be prepared by standardtechniques. For example, the free-base form of a compound can bedissolved in a suitable solvent, such as an aqueous or aqueous-alcoholsolution containing the appropriate acid and then isolated byevaporating the solution. In another example, a salt can be prepared byreacting the free base and acid in an organic solvent. If the particularcompound is an acid, the desired pharmaceutically acceptable salt may beprepared by any suitable method, for example, treatment of the free acidwith an appropriate inorganic or organic base.

(d) Other Compound Forms

In the case of agents that are solids, it is understood by those skilledin the art that the compounds and salts may exist in different crystalor polymorphic forms, or may be formulated as co-crystals, or may be inan amorphous form, or may be any combination thereof (e.g. partiallycrystalline, partially amorphous, or mixtures of polymorphs) all ofwhich are intended to be within the scope of the present disclosure andspecified formulae. Whereas salts are formed by acid/base addition, i.e.a free base or free acid of the compound of interest forms an acid/basereaction with a corresponding addition base or addition acid,respectively, resulting in an ionic charge interaction, co-crystals area new chemical species that is formed between neutral compounds,resulting in the compound and an additional molecular species in thesame crystal structure.

In some instances, compounds of the present disclosure are complexedwith an acid or a base, including base addition salts such as ammonium,diethylamine, ethanolamine, ethylenediamine, diethanolamine,t-butylamine, piperazine, meglumine; acid addition salts, such asacetate, acetylsalicylate, besylate, camsylate, citrate, formate,fumarate, glutarate, hydrochlorate, maleate, mesylate, nitrate, oxalate,phosphate, succinate, sulfate, tartrate, thiocyanate and tosylate; andamino acids such as alanine, arginine, asparagine, aspartic acid,cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine,leucine, lysine, methionine, phenylalanine, proline, serine, threonine,tryptophan, tyrosine or valine. In combining the compound of the presentdisclosure with the acid or base, an amorphous complex is preferablyformed rather than a crystalline material such as a typical salt orco-crystal. In some instances, the amorphous form of the complex isfacilitated by additional processing, such as by spray-drying,mechanochemical methods such as roller compaction, or microwaveirradiation of the parent compound mixed with the acid or base. Suchmethods may also include addition of ionic and/or non-ionic polymersystems, including, but not limited to, hydroxypropyl methyl celluloseacetate succinate (HPMCAS) and methacrylic acid copolymer (e.g.Eudragit® L100-55), that further stabilize the amorphous nature of thecomplex. Such amorphous complexes provide several advantages. Forexample, lowering of the melting temperature relative to the free basefacilitates additional processing, such as hot melt extrusion, tofurther improve the biopharmaceutical properties of the compound. Also,the amorphous complex is readily friable, which provides improvedcompression for loading of the solid into capsule or tablet form.

Additionally, the formulae are intended to cover hydrated or solvated aswell as unhydrated or unsolvated forms of the identified structures. Forexample, the indicated compounds include both hydrated and non-hydratedforms. Other examples of solvates include the structures in combinationwith a suitable solvent, such as isopropanol, ethanol, methanol,dimethyl sulfoxide, ethyl acetate, acetic acid, or ethanolamine.

IV. Formulations and Administration

In another aspect, the present disclosure provides pharmaceuticalcompositions comprising/including a pharmaceutically acceptable carrier,excipient and/or diluent and a compound of the present disclosuredescribed herein or a pharmaceutically acceptable salt or solvatethereof. In an exemplary embodiment, the present disclosure provides apharmaceutical formulation comprising/including a compound as describedherein. In some embodiments, the present disclosure providespharmaceutical composition comprising/including a compound of Formulae(I) or (II); or a pharmaceutically acceptable salt, a solvate, atautomer, an isomer, or a deuterated analog of Formulae (I) or (II); orany of the compounds in Table I, and a pharmaceutically acceptablecarrier, excipient and/or diluents.

The methods and compounds will typically be used in therapy for humansubjects. However, they may also be used to treat similar or identicalindications in other animal subjects. Compounds described herein can beadministered by different routes, including injection (i.e. parenteral,including intravenous, intraperitoneal, subcutaneous, andintramuscular), oral, transdermal, transmucosal, rectal, or inhalantSuch dosage forms should allow the compound to reach target cells. Otherfactors are well known in the art, and include considerations such astoxicity and dosage forms that retard the compound or composition fromexerting its effects. Techniques and formulations generally may be foundin Remington: The Science and Practice of Pharmacy, 21^(st) edition,Lippincott, Williams and Wilkins, Philadelphia, Pa., 2005 (herebyincorporated by reference herein).

In some embodiments, compositions will comprise pharmaceuticallyacceptable carriers or excipients, such as fillers, binders,disintegrants, glidants, lubricants, complexing agents, solubilizers,and surfactants, which may be chosen to facilitate administration of thecompound by a particular route. Examples of carriers include calciumcarbonate, calcium phosphate, various sugars such as lactose, glucose,or sucrose, types of starch, cellulose derivatives, gelatin, lipids,liposomes, nanoparticles, and the like. Carriers also includephysiologically compatible liquids as solvents or for suspensions,including, for example, sterile solutions of water for injection (WFI),saline solution, dextrose solution, Hank's solution, Ringer's solution,vegetable oils, mineral oils, animal oils, polyethylene glycols, liquidparaffin, and the like. Excipients may also include, for example,colloidal silicon dioxide, silica gel, talc, magnesium silicate, calciumsilicate, sodium aluminosilicate, magnesium trisilicate, powderedcellulose, macrocrystalline cellulose, carboxymethyl cellulose,cross-linked sodium carboxymethylcellulose, sodium benzoate, calciumcarbonate, magnesium carbonate, stearic acid, aluminum stearate, calciumstearate, magnesium stearate, zinc stearate, sodium stearyl fumarate,syloid, stearowet C, magnesium oxide, starch, sodium starch glycolate,glyceryl monostearate, glyceryl dibehenate, glyceryl palmitostearate,hydrogenated vegetable oil, hydrogenated cotton seed oil, castor seedoil mineral oil, polyethylene glycol (e.g. PEG 400-8000),polyoxyethylene glycol, poloxamers, povidone, crospovidone,croscarmellose sodium, alginic acid, casein, methacrylic aciddivinylbenzene copolymer, sodium docusate, cyclodextrins (e.g.2-hydroxypropyl-.delta.-cyclodextrin), polysorbates (e.g. polysorbate80), cetrimide, TPGS (d-alpha-tocopheryl polyethylene glycol 1000succinate), magnesium lauryl sulfate, sodium lauryl sulfate,polyethylene glycol ethers, di-fatty acid ester of polyethylene glycols,or a polyoxyalkylene sorbitan fatty acid ester (e.g., polyoxyethylenesorbitan ester Tween®), polyoxyethylene sorbitan fatty acid esters,sorbitan fatty acid ester, e.g. a sorbitan fatty acid ester from a fattyacid such as oleic, stearic or palmitic acid, mannitol, xylitol,sorbitol, maltose, lactose, lactose monohydrate or lactose spray dried,sucrose, fructose, calcium phosphate, dibasic calcium phosphate,tribasic calcium phosphate, calcium sulfate, dextrates, dextran,dextrin, dextrose, cellulose acetate, maltodextrin, simethicone,polydextrosem, chitosan, gelatin, HPMC (hydroxypropyl methylcelluloses), HPC (hydroxypropyl cellulose), hydroxyethyl cellulose, andthe like.

Pharmaceutical formulations may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to700 mg, more preferably 5 mg to 100 mg of a compound of the presentdisclosure (as a free-base, solvate (including hydrate) or salt, in anyform), depending on the condition being treated, the route ofadministration, and the age, weight and condition of the patient.Preferred unit dosage formulations are those containing a daily dose,weekly dose, monthly dose, a sub-dose or an appropriate fractionthereof, of an active ingredient. Furthermore, such pharmaceuticalformulations may be prepared by any of the methods well known in thepharmacy art.

Pharmaceutical formulations may be adapted for administration by anyappropriate route, for example by the oral (including capsules, tablets,liquid-filled capsules, disintegrating tablets, immediate, delayed andcontrolled release tablets, oral strips, solutions, syrups, buccal andsublingual), rectal, nasal, inhalation, topical (including transdermal),vaginal or parenteral (including subcutaneous, intramuscular,intravenous or intradermal) route. Such formulations may be prepared byany method known in the art of pharmacy, for example by bringing intoassociation the active ingredient with the carrier(s), excipient(s) ordiluent. Generally, the carrier, excipient or diluent employed in thepharmaceutical formulation is “non-toxic,” meaning that it/they is/aredeemed safe for consumption in the amount delivered in thepharmaceutical composition, and “inert” meaning that it/they does/do notappreciably react with or result in an undesired effect on thetherapeutic activity of the active ingredient.

In some embodiments, oral administration may be used. Pharmaceuticalpreparations for oral use can be formulated into conventional oraldosage forms such as discreet units capsules, tablets, and liquidpreparations such as syrups, elixirs, and concentrated drops. Compoundsdescribed herein may be combined with solid excipients, optionallygrinding a resulting mixture, and processing the mixture of granules,after adding suitable auxiliaries, if desired, to obtain, for example,tablets, coated tablets, hard capsules, soft capsules, solutions (e.g.aqueous, alcoholic, or oily solutions) and the like. Suitable excipientsare, in particular, fillers such as sugars, including lactose, glucose,sucrose, mannitol, or sorbitol; cellulose preparations, for example,corn starch, wheat starch, rice starch, potato starch, gelatin, gumtragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodiumcarboxymethylcellulose (CMC), and/or polyvinylpyrrolidone (PVP:povidone); oily excipients, including vegetable and animal oils, such assunflower oil, olive oil, or cod-liver oil. The oral dosage formulationsmay also contain disintegrating agents, such as the cross-linkedpolyvinylpyrrolidone, agar, or alginic acid, or a salt thereof such assodium alginate; a lubricant, such as talc or magnesium stearate; aplasticizer, such as glycerol or sorbitol; a sweetening such as sucrose,fructose, lactose, or aspartame; a natural or artificial flavoringagent, such as peppermint, oil of wintergreen, or cherry flavoring; ordye-stuffs or pigments, which may be used for identification orcharacterization of different doses or combinations, such as unitdosages. Also provided are dragee cores with suitable coatings. For thispurpose, concentrated sugar solutions may be used, which may optionallycontain, for example, gum arabic, talc, poly-vinylpyrrolidone, carbopolgel, polyethylene glycol, and/or titanium dioxide, lacquer solutions,and suitable organic solvents or solvent mixtures. Oral fluids such assolutions, syrups and elixirs can be prepared in dosage unit form sothat a given quantity contains a predetermined amount of the compound.

Pharmaceutical preparations that can be used orally include push-fitcapsules made of gelatin (“gelcaps”), as well as soft, sealed capsulesmade of gelatin, and a plasticizer, such as glycerol or sorbitol. Thepush-fit capsules can contain the active ingredients in admixture withfiller such as lactose, binders such as starches, and/or lubricants suchas talc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols.

In some embodiments, injection (parenteral administration) may be used,e.g., intramuscular, intravenous, intraperitoneal, and/or subcutaneous.Compounds described herein for injection may be formulated in sterileliquid solutions, preferably in physiologically compatible buffers orsolutions, such as saline solution, Hank's solution, or Ringer'ssolution. Dispersions may also be prepared in non-aqueous solutions,such as glycerol, propylene glycol, ethanol, liquid polyethyleneglycols, triacetin, and vegetable oils. Solutions may also contain apreservative, such as methylparaben, propylparaben, chlorobutanol,phenol, sorbic acid, thimerosal, and the like. In addition, thecompounds may be formulated in solid form, including, for example,lyophilized forms, and redissolved or suspended prior to use. Theformulations may be presented in unit-dose or multi-dose containers, forexample sealed ampoules and vials, and may be stored in a freeze-dried(lyophilized) condition requiring only the addition of the sterileliquid carrier, for example water for injection, immediately prior touse.

In some embodiments, transmucosal, topical or transdermal administrationmay be used. In such formulations of compounds described herein,penetrants appropriate to the barrier to be permeated are used. Suchpenetrants are generally known in the art, and include, for example, fortransmucosal administration, bile salts and fusidic acid derivatives. Inaddition, detergents may be used to facilitate permeation. Transmucosaladministration, for example, may be through nasal sprays orsuppositories (rectal or vaginal). Compositions of compounds describedherein for topical administration may be formulated as oils, creams,lotions, ointments, and the like by choice of appropriate carriers knownin the art. Suitable carriers include vegetable or mineral oils, whitepetrolatum (white soft paraffin), branched chain fats or oils, animalfats and high molecular weight alcohol (greater than C₁₂). In someembodiments, carriers are selected such that the active ingredient issoluble. Emulsifiers, stabilizers, humectants and antioxidants may alsobe included as well as agents imparting color or fragrance, if desired.Creams for topical application are preferably formulated from a mixtureof mineral oil, self-emulsifying beeswax and water in which mixture theactive ingredient, dissolved in a small amount of solvent (e.g., anoil), is admixed. Additionally, administration by transdermal means maycomprise a transdermal patch or dressing such as a bandage impregnatedwith an active ingredient and optionally one or more carriers ordiluents known in the art. To be administered in the form of atransdermal delivery system, the dosage administration will becontinuous rather than intermittent throughout the dosage regimen.

In some embodiments, compounds are administered as inhalants Compoundsdescribed herein may be formulated as dry powder or a suitable solution,suspension, or aerosol. Powders and solutions may be formulated withsuitable additives known in the art. For example, powders may include asuitable powder base such as lactose or starch, and solutions maycomprise propylene glycol, sterile water, ethanol, sodium chloride andother additives, such as acid, alkali and buffer salts. Such solutionsor suspensions may be administered by inhaling via spray, pump,atomizer, or nebulizer, and the like. The compounds described herein mayalso be used in combination with other inhaled therapies, for examplecorticosteroids such as fluticasone proprionate, beclomethasonedipropionate, triamcinolone acetonide, budesonide, and mometasonefuroate; beta agonists such as albuterol, salmeterol, and formoterol;anticholinergic agents such as ipratroprium bromide or tiotropium;vasodilators such as treprostinal and iloprost; enzymes such as DNAase;therapeutic proteins; immunoglobulin antibodies; an oligonucleotide,such as single or double stranded DNA or RNA, siRNA; antibiotics such astobramycin; muscarinic receptor antagonists; leukotriene antagonists;cytokine antagonists; protease inhibitors; cromolyn sodium; nedocrilsodium; and sodium cromoglycate.

The amounts of various compounds to be administered can be determined bystandard procedures taking into account factors such as the compoundactivity (in vitro, e.g. the compound IC₅₀ vs. target, or in vivoactivity in animal efficacy models), pharmacokinetic results in animalmodels (e.g. biological half-life or bioavailability), the age, size,and weight of the subject, and the disorder associated with the subject.The importance of these and other factors are well known to those ofordinary skill in the art. Generally, a dose will be in the range ofabout 0.01 to 50 mg/kg, also about 0.1 to 20 mg/kg of the subject beingtreated. Multiple doses may be used.

The compounds described herein may also be used in combination withother therapies for treating the same disease. Such combination useincludes administration of the compounds and one or more othertherapeutics at different times, or co-administration of the compoundand one or more other therapies. In some embodiments, dosage may bemodified for one or more of the compounds of the present disclosure orother therapeutics used in combination, e.g., reduction in the amountdosed relative to a compound or therapy used alone, by methods wellknown to those of ordinary skill in the art.

It is understood that use in combination includes use with othertherapies, drugs, medical procedures etc., where the other therapy orprocedure may be administered at different times (e.g. within a shorttime, such as within hours (e.g. 1, 2, 3, 4-24 hours), or within alonger time (e.g. 1-2 days, 2-4 days, 4-7 days, 1-4 weeks)) than acompound described herein, or at the same time as a compound describedherein. Use in combination also includes use with a therapy or medicalprocedure that is administered once or infrequently, such as surgery,along with a compound described herein administered within a short timeor longer time before or after the other therapy or procedure. In someembodiments, the present disclosure provides for delivery of a compounddescribed herein and one or more other drug therapeutics delivered by adifferent route of administration or by the same route ofadministration. The use in combination for any route of administrationincludes delivery of a compound described herein and one or more otherdrug therapeutics delivered by the same route of administration togetherin any formulation, including formulations where the two compounds arechemically linked in such a way that they maintain their therapeuticactivity when administered. In one aspect, the other drug therapy may beco-administered with a compound described herein. Use in combination byco-administration includes administration of co-formulations orformulations of chemically joined compounds, or administration of two ormore compounds in separate formulations within a short time of eachother (e.g. within an hour, 2 hours, 3 hours, up to 24 hours),administered by the same or different routes. Co-administration ofseparate formulations includes co-administration by delivery via onedevice, for example the same inhalant device, the same syringe, etc., oradministration from separate devices within a short time of each other.Co-formulations of a compound described herein and one or moreadditional drug therapies delivered by the same route includespreparation of the materials together such that they can be administeredby one device, including the separate compounds combined in oneformulation, or compounds that are modified such that they arechemically joined, yet still maintain their biological activity. Suchchemically joined compounds may have a linkage that is substantiallymaintained in vivo, or the linkage may break down in vivo, separatingthe two active components. The compounds as disclosed herein may be usedin adjuvant or neoadjuvant therapy in combination with other therapy ortherapeutic agents as described herein.

V. Disease Indications and Modulations of Bromodomains

Exemplary Diseases Associated with Bromodomains

Members of the BET (Bromodomain and Extra Terminal) family ofbromodomain proteins (BRD2, BRD3, BRD4 and BRDT) have been associatedwith a variety of disorders including neurological diseases, autoimmuneand inflammatory diseases, metabolic diseases (Muller et al. Expert Rev.Mol. Med. 2011 Sep. 13; 13:e29; Prinjha et al. Trends Pharmacol. Sci.2012, 33, 146-153; Belkina et al. I Immunol. 2013, 190, 3670-3678; andBelkina et al. Nature Rev. Cancer 2012, 12, 465-477) and cancers(Alsarraj et al. International Journal of Breast Cancer 2012, 1-7;Barbieri et al. Briefings in Functional Genomics 2013, 1-12; Blobel etal. Cancer Cell 2011, 20, 287-288; Dang Cell 2012, 149, 22-35). Inaddition, some viruses make use of these proteins to tether theirgenomes to the host cells chromatin, as part of the process of viralreplication (You et al Cell, 2004 117, 349-60).

The compounds of Formulae (I) or (II), or any of the compounds asdescribed herein, are useful for treating disorders related to one ormore proteins involved in epigenetic regulation, such as proteinscontaining acetyl-lysine recognition motifs, i.e., bromodomains (e.g.,BET proteins, such as BRD2, BRD3, BRD4, and/or BRDT), and e.g., diseasesrelated to abnormal expression of bromodomains, including cellproliferative disorders, cancers, chronic autoimmune, inflammatoryconditions, among others.

The presence of bromodomains has been associated with a number ofdifferent types of cancers, and other diseases and conditions, asdescribed below. Bromodomain inhibitors such as compounds of Formulae(I) or (II); or a pharmaceutically acceptable salt, a solvate, atautomer, an isomer, or a deuterated analog of Formulae (I) or (II); allembodiments of Formulae I or II described herein; or any of thecompounds as described in Table I, are useful in the treatment ofsystemic or tissue inflammation, inflammatory responses to infection orhypoxia, cellular activation and proliferation, lipid metabolism,fibrosis and in the prevention and treatment of viral infections.

Bromodomain inhibitors such as compounds of Formulae (I) or (II); or apharmaceutically acceptable salt, a solvate, a tautomer, an isomer, or adeuterated analog of Formulae (I) or (II); all embodiments of Formulae Ior II described herein; or any of the compounds as described in Table I,are useful in the prevention and treatment of chronic autoimmune andinflammatory conditions such as rheumatoid arthritis, osteoarthritis,acute gout, psoriasis, systemic lupus erythematosus, multiple sclerosis,inflammatory bowel disease (Crohn's disease and Ulcerative colitis),asthma, chronic obstructive airways disease, pneumonitis, myocarditis,pericarditis, myositis, eczema, dermatitis, alopecia, vitiligo, bullousskin diseases, nephritis, vasculitis, atherosclerosis, Alzheimer'sdisease, depression, retinitis, uveitis, scleritis, hepatitis,pancreatitis, primary biliary cirrhosis, sclerosing cholangitis,Addison's disease, hypophysitis, thyroiditis, type I diabetes and acuterejection of transplanted organs.

Bromodomain inhibitors such as compounds of Formulae (I) or (II); or apharmaceutically acceptable salt, a solvate, a tautomer, an isomer, or adeuterated analog of Formulae (I) or (II); all embodiments of Formulae Ior II described herein; or any of the compounds as described in Table I,are useful in the prevention and treatment of acute inflammatoryconditions, including, but not limiting to, such as acute gout, giantcell arteritis, nephritis including lupus nephritis, vasculitis withorgan involvement such as glomerulonephritis, vasculitis including giantcell arteritis, Wegener's granulomatosis, Polyarteritis nodosa, Behcet'sdisease, Kawasaki disease, Takayasu's Arteritis, vasculitis with organinvolvement and acute rejection of transplanted organs.

Bromodomain inhibitors such as compounds of Formulae (I) or (II); or apharmaceutically acceptable salt, a solvate, a tautomer, an isomer, or adeuterated analog of Formulae (I) or (II); all embodiments of Formulae Ior II described herein; or any of the compounds as described in Table I,are useful in the prevention and treatment of autoimmune andinflammatory diseases or conditions which involve inflammatory responsesto infections with bacteria, viruses, such as herpes virus, humanpapilloma virus, adenovirus and poxvirus and other DNA viruses; fungi,parasites or their toxins, such as sepsis, sepsis syndrome, septicshock, endotoxaemia, systemic inflammatory response syndrome (SIRS),multi-organ dysfunction syndrome, toxic shock syndrome, acute lunginjury, ARDS (adult respiratory distress syndrome), acute renal failure,fulminant hepatitis, burns, acute pancreatitis, post-surgical syndromes,sarcoidosis, Herxheimer reactions, encephalitis, myelitis, meningitis,malaria and SIRS associated with viral infections such as influenza,herpes zoster, herpes simplex and coronavirus.

Bromodomain inhibitors such as compounds of Formulae (I) or (II); or apharmaceutically acceptable salt, a solvate, a tautomer, an isomer, or adeuterated analog of Formulae (I) or (II); all embodiments of Formulae Ior II described herein; or any of the compounds as described in Table I,are useful in the prevention and treatment of diseases or conditionsassociated with ischemia-reperfusion injury, including, but not limitingto, myocardial infarction, cerebro-vascular ischemia (stroke), acutecoronary syndromes, renal reperfusion injury, organ transplantation,coronary artery bypass grafting, cardio-pulmonary bypass procedures,pulmonary, renal, hepatic, gastro-intestinal or peripheral limbembolism.

Bromodomain inhibitors such as compounds of Formulae (I) or (II); or apharmaceutically acceptable salt, a solvate, a tautomer, an isomer, or adeuterated analog of Formulae (I) or (II); all embodiments of Formulae Ior II described herein; or any of the compounds as described in Table I,are useful in the prevention and treatment of hypercholesterolemia,atherosclerosis and Alzheimer's disease.

Bromodomain inhibitors such as compounds of Formulae (I) or (II); or apharmaceutically acceptable salt, a solvate, a tautomer, an isomer, or adeuterated analog of Formulae (I) or (II); all embodiments of Formulae Ior II described herein; or any of the compounds as described in Table I,are useful in the prevention and treatment of cancers including, but notlimiting to, hematological, epithelial including lung, breast and coloncarcinomas, midline carcinomas, mesenchymal, hepatic, renal,neurological tumors, adrenal cancer, acinic cell carcinoma, acousticneuroma, acral lentiginous melanoma, acrospiroma, acute eosinophilicleukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acutemegakaryoblastic leukemia, acute monocytic leukemia, acute promyelocyticleukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoidodontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm,adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aggressiveNK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma,alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large celllymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma,angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rhabdoidtumor, B-cell chronic lymphocytic leukemia, B-cell prolymphocyticleukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer,bladder cancer, blastoma, bone cancer, Brenner tumor, Brown tumor,Burkitt's lymphoma, breast cancer, brain cancer, carcinoma, carcinoma insitu, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma,chondroma, chordoma, choriocarcinoma, choroid plexus papilloma,clear-cell sarcoma of the kidney, craniopharyngioma, cutaneous T-celllymphoma, cervical cancer, colorectal cancer, Degos disease,desmoplastic small round cell tumor, diffuse large B-cell lymphoma,dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonalcarcinoma, endocrine gland neoplasm, endodermal sinus tumor,enteropathy-associated T-cell lymphoma, esophageal cancer, fetus infetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroidcancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor,gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumorof the bone, glial tumor, glioblastoma multiforme, glioma, gliomatosiscerebri, glucagonoma, gonadoblastoma, granulosa cell tumor,gynandroblastoma, gallbladder cancer, gastric cancer, hairy cellleukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma,hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma,Hodgkin's lymphoma, non-Hodgkin'lymphoma, invasive lobular carcinoma,intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna,lethal midline carcinoma, leukemia, leydig cell tumor, liposarcoma, lungcancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma,acute lymphocytic leukemia, acute myelogenous leukemia, chroniclymphocytic leukemia, liver cancer, small cell lung cancer, non-smallcell lung cancer, MALT lymphoma, malignant fibrous histiocytoma,malignant peripheral nerve sheath tumor, malignant triton tumor, mantlecell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia,mediastinal germ cell tumor, medullary carcinoma of the breast,medullary thyroid cancer, medulloblastoma, melanoma, meningioma, merkelcell cancer, mesothelioma, metastatic urothelial carcinoma, mixedMullerian tumor, mucinous tumor, multiple myeloma, muscle tissueneoplasm, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma,nasopharyngeal carcinoma, neurinoma, neuroblastoma, neurofibroma,neuroma, nodular melanoma, ocular cancer, oligoastrocytoma,oligodendroglioma, oncocytoma, optic nerve sheath meningioma, opticnerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor,papillary thyroid cancer, paraganglioma, pinealoblastoma, pineocytoma,pituicytoma, pituitary adenoma, pituitary tumor, plasmacytoma,polyembryoma, precursor T-lymphoblastic lymphoma, primary centralnervous system lymphoma, primary effusion lymphoma, primary peritonealcancer, prostate cancer, pancreatic cancer, pharyngeal cancer,pseudomyxoma peritonei, renal cell carcinoma, renal medullary carcinoma,retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation,rectal cancer, sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor,sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer,small blue round cell tumors, small cell carcinoma, soft tissue sarcoma,somatostatinoma, soot wart, spinal tumor, splenic marginal zonelymphoma, squamous cell carcinoma, synovial sarcoma, Sezary's disease,small intestine cancer, squamous carcinoma, stomach cancer, T-celllymphoma, testicular cancer, thecoma, thyroid cancer, transitional cellcarcinoma, throat cancer, urachal cancer, urogenital cancer, urothelialcarcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visualpathway glioma, vulvar cancer, vaginal cancer, Waldenstrom'smacroglobulinemia, Warthin's tumor, and Wilms' tumor.

Bromodomain Activity Assays

A number of different assays for bromodomain activity can be utilizedfor assaying for active modulators and/or determining specificity of amodulator for a particular bromodomain or group. In addition to theassay mentioned in the Examples below, one of ordinary skill in the artwill know of other assays that can be utilized and can modify an assayfor a particular application.

In certain embodiments, compounds of Formulae (I) or (II), or acompounds set forth in Table I. have an IC₅₀ of less than less than 100nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM,or less than 1 nM as determined in a generally accepted bromodomainactivity assay or a bromodomain activity assay as described herein. Insome embodiments, the assay for measuring bromodomain activity includesan assay (e.g., biochemical or cell-bases assays) such as described inExample 6 or an assay known in the art.

Modulation of Bromodomain

In another aspect, the present disclosure provides a method formodulating or inhibiting a bromodomain protein. The method includesadministering to a subject an effective amount of a compound of acompounds of Formulae (I) or (II); or a pharmaceutically acceptablesalt, a solvate, a tautomer, an isomer, or a deuterated analog ofFormulae (I) or (II); or any of the compounds as described in Table I;or a composition comprising a compound of any of the formulae asdescribed herein, thereby, modulating or inhibiting the bromodomain. Insome embodiments, the method includes contacting a cell in vivo or invitro with a compound of Formulae (I) or (II); or a pharmaceuticallyacceptable salt, a solvate, a tautomer, an isomer, or a deuteratedanalog of Formulae (I) or (II); all embodiments of Formulae I or IIdescribed herein; or any of the compounds as described in Table I, or acomposition comprising a compound of any of the formulae as describedherein.

VI. Methods for Treating Conditions Mediated by Bromodomain

In another aspect, the present disclosure provides a method for treatinga subject suffering from or at risk of a bromodomain mediated diseasesor conditions, wherein inhibition of bromodomain plays a role orprovides a benefit. The method includes administering to the subject aneffective amount of a a compound of Formulae (I) or (II); or apharmaceutically acceptable salt, a solvate, a tautomer, an isomer, or adeuterated analog of Formulae (I) or (II); or any of the compounds asdescribed in Table I, or a composition comprising a compound of any ofthe formulas as described herein. In certain embodiments, the methodinvolves administering to the subject an effective amount of any one ormore compound(s) as described herein in combination with one or moreother therapies or therapeutic agents for the disease or condition. Insome embodiments, the method involves administering to the subject aneffective amount of any one or more compound(s) as described herein incombination with one or more other therapeutic agents for the disease orcondition.

In some embodiments, the present disclosure provides a method ofsuppressing undesired proliferation of tumor cells mediated bybromodomain. The method includes contacting tumor cells with aneffective amount of a compound of a compound of any of Formulae (I) or(II), or any of the compounds set forth in Table I, or apharmaceutically acceptable salt, hydrate, solvate, tautomer or isomerthereof, or a composition comprising a compound as described herein. Insome instances, the tumor cells are mediated by BET protein, BRD4protein or a mutant thereof.

In certain embodiments, the present disclosure provides a method oftreating a patient, where inhibition of bromodomain (e.g., BET proteinor BRD4 protein) provides a benefit. The method includes administeringto the patient in need thereof an effective amount of a compound of anyof Formulae (I) or (II), or any of the compounds set forth in Table I,or a pharmaceutically acceptable salt, hydrate, solvate, tautomer orisomer thereof, or a composition comprising a compound as describedherein.

In some embodiments, the present disclosure provides methods fortreating a subject suffering or at risk of a disease or conditionmediated by a bromodomain, said method comprising administering to thesubject in need thereof an effective amount of a compound of Formulae(I) or (II); or a pharmaceutically acceptable salt, a solvate, atautomer, an isomer, or a deuterated analog of Formulae (I) or (II); orany of the compounds in Table I, or any of the pharmaceuticalcompositions thereof described herein, and the disease or condition is acancer, an autoimmune condition, an inflammatory condition or acombination thereof.

In some embodiments, the diseases or conditions treatable with thecompounds of the present disclosure include, but are not limited to, acancer, e.g., hematological, epithelial including lung, breast and coloncarcinomas, midline carcinomas, mesenchymal, hepatic, renal,neurological tumors, adrenal cancer, acinic cell carcinoma, acousticneuroma, acral lentiginous melanoma, acrospiroma, acute eosinophilicleukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acutemegakaryoblastic leukemia, acute monocytic leukemia, acute promyelocyticleukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoidodontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm,adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aggressiveNK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma,alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large celllymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma,angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rhabdoidtumor, B-cell chronic lymphocytic leukemia, B-cell prolymphocyticleukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer,bladder cancer, blastoma, bone cancer, Brenner tumor, Brown tumor,Burkitt's lymphoma, breast cancer, brain cancer, carcinoma, carcinoma insitu, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma,chondroma, chordoma, choriocarcinoma, choroid plexus papilloma,clear-cell sarcoma of the kidney, craniopharyngioma, cutaneous T-celllymphoma, cervical cancer, colorectal cancer, Degos disease,desmoplastic small round cell tumor, diffuse large B-cell lymphoma,dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonalcarcinoma, endocrine gland neoplasm, endodermal sinus tumor,enteropathy-associated T-cell lymphoma, esophageal cancer, fetus infetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroidcancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor,gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumorof the bone, glial tumor, glioblastoma multiforme, glioma, gliomatosiscerebri, glucagonoma, gonadoblastoma, granulosa cell tumor,gynandroblastoma, gallbladder cancer, gastric cancer, hairy cellleukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma,hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma,Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma,intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna,lethal midline carcinoma, leukemia, leydig cell tumor, liposarcoma, lungcancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma,acute lymphocytic leukemia, acute myelogenous leukemia, chroniclymphocytic leukemia, liver cancer, small cell lung cancer, non-smallcell lung cancer, MALT lymphoma, malignant fibrous histiocytoma,malignant peripheral nerve sheath tumor, malignant triton tumor, mantlecell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia,mediastinal germ cell tumor, medullary carcinoma of the breast,medullary thyroid cancer, medulloblastoma, melanoma, meningioma, merkelcell cancer, mesothelioma, metastatic urothelial carcinoma, mixedMullerian tumor, mucinous tumor, multiple myeloma, muscle tissueneoplasm, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma,nasopharyngeal carcinoma, neurinoma, neuroblastoma, neurofibroma,neuroma, nodular melanoma, ocular cancer, oligoastrocytoma,oligodendroglioma, oncocytoma, optic nerve sheath meningioma, opticnerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor,papillary thyroid cancer, paraganglioma, pinealoblastoma, pineocytoma,pituicytoma, pituitary adenoma, pituitary tumor, plasmacytoma,polyembryoma, precursor T-lymphoblastic lymphoma, primary centralnervous system lymphoma, primary effusion lymphoma, primary peritonealcancer, prostate cancer, pancreatic cancer, pharyngeal cancer,pseudomyxoma peritonei, renal cell carcinoma, renal medullary carcinoma,retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation,rectal cancer, sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor,sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer,small blue round cell tumors, small cell carcinoma, soft tissue sarcoma,somatostatinoma, soot wart, spinal tumor, splenic marginal zonelymphoma, squamous cell carcinoma, synovial sarcoma, Sezary's disease,small intestine cancer, squamous carcinoma, stomach cancer, T-celllymphoma, testicular cancer, thecoma, thyroid cancer, transitional cellcarcinoma, throat cancer, urachal cancer, urogenital cancer, urothelialcarcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visualpathway glioma, vulvar cancer, vaginal cancer, Waldenstrom'smacroglobulinemia, Warthin's tumor, and Wilms' tumor. In certainembodiments, the cancer treatable with the compounds of the presentdisclosure is selected from adenocarcinoma, adult T-cellleukemia/lymphoma, bladder cancer, blastoma, bone cancer, breast cancer,brain cancer, carcinoma, myeloid sarcoma, cervical cancer, colorectalcancer, esophageal cancer, gastrointestinal cancer, glioblastomamultiforme, glioma, gallbladder cancer, gastric cancer, head and neckcancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, intestinal cancer,kidney cancer, laryngeal cancer, leukemia, lung cancer, lymphoma, livercancer, small cell lung cancer, non-small cell lung cancer,mesothelioma, multiple myeloma, ocular cancer, optic nerve tumor, oralcancer, ovarian cancer, pituitary tumor, primary central nervous systemlymphoma, prostate cancer, pancreatic cancer, pharyngeal cancer, renalcell carcinoma, rectal cancer, sarcoma, skin cancer, spinal tumor, smallintestine cancer, stomach cancer, T-cell lymphoma, testicular cancer,thyroid cancer, throat cancer, urogenital cancer, urothelial carcinoma,uterine cancer, vaginal cancer, or Wilms' tumor. In other embodiments,the cancers or tumors treatable with the compounds of the presentdisclosure include benign soft tissue tumors, bone tumors, brain andspinal tumors, eyelid and orbital tumors, granuloma, lipoma, meningioma,multiple endocrine neoplasia, nasal polyps, pituitary tumors,prolactinoma, pseudotumor cerebri, seborrheic keratoses, stomach polyps,thyroid nodules, cystic neoplasms of the pancreas, hemangiomas, vocalcord nodules, polyps, and cysts, Castleman disease, chronic pilonidaldisease, dermatofibroma, pilar cyst, pyogenic granuloma, and juvenilepolyposis syndrome. In another embodiment, the diseases or conditionstreatable with the compounds of the present disclosure include non-smallcell lung cancer, small cell lung cancer, ovarian cancer, melanoma,midline carcinomas, breast cancer, lymphomas, neuroblastoma, orcastration resistant prostate cancer, myelofibrosis, myelodysplasticsyndromes, or acute myeloid leukemia. In another embodiment, thediseases or conditions treatable with the compounds of the presentdisclosure include non-small cell lung cancer, small cell lung cancer,ovarian cancer, melanoma, neuroblastoma, and castration resistantprostate cancer.

In another embodiment of this disclosure, the disease or condition thatcan be treated by the compounds of the present disclosure is a lysosomalstorage disorder. Non-limiting examples of lysosomal storage disordersinclude mucolipodosis, alpha-mannosidosis; aspartylglucosaminuria;Batten disease; beta-mannosidosis; cystinosis; Danon disease; Fabrydisease; Farber disease; fucosidosis; galactosialidosis; Gaucherdisease; gangliosidosis (e.g., GM1 gangliosidosis and GM2-gangliosidosisAB variant); Krabbe disease; metachromatic leukodystrophy;mucopolysaccharidoses disorders (e.g., MPS 1—Hurler syndrome, MPSII—Hunter syndrome, MPS III—Sanfilippo (A,B,C,D), MPS IVA—Morquio, MPSIX—hyaluronidase, deficiency, MPS VI—Maroteaux-Lamy, or MPS VII—Slysyndrome); mucolipidosis type I (Sialidosis); Mucolipidosis type II(I-Cell disease); Mucolipidosis type III (Pseudo-Hurler polydystrophy);Mucolipidosis type IV; multiple sulfatase deficiency; Niemann-Pick typesA, B, C; Pompe disease (glycogen storage disease); pycnodysostosis;Sandhoff disease; Schindler disease; Salla disease/sialic acid storagedisease; Tay-Sachs; and Wolman disease

In some embodiments, the present disclosure provides methods fortreating an autoimmune and inflammatory disease or condition in asubject by administration of an effective amount of a compound ofFormulae (I) or (II); or a pharmaceutically acceptable salt, a solvate,a tautomer, an isomer, or a deuterated analog of Formulae (I) or (II);or any of the compounds in Table I, or any of the pharmaceuticalcompositions thereof described herein. The diseases or conditionstreatable with the compounds of the present disclosure include, but arenot limited to, inflammatory pelvic disease, urethritis, skin sunburn,sinusitis, pneumonitis, encephalitis, meningitis, myocarditis,nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis,dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis,agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowelsyndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection,hyperacute rejection of transplanted organs, asthma, allergic rhinitis,chronic obstructive pulmonary disease (COPD), autoimmune polyglandulardisease (also known as autoimmune polyglandular syndrome), autoimmunealopecia, pernicious anemia, glomerulonephritis, dermatomyositis,multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic andthrombocytopenic states, Goodpasture's syndrome, atherosclerosis,Addison's disease, Parkinson's disease, Alzheimer's disease, Type Idiabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoidarthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis,chronic idiopathic thrombocytopenic purpura, Waldenstrommacroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopicdermatitis, degenerative joint disease, vitiligo, autoimmunehypopituitarism, Guillain-Barre syndrome, Behcet's disease,scleracierma, mycosis fungoides, acute inflammatory responses (such asacute respiratory distress syndrome and ischemia/reperfusion injury),and Graves' disease. In certain embodiments, the diseases and conditionstreatable with the compounds of the present disclosure include systemicor tissue inflammation, inflammatory responses to infection or hypoxia,cellular activation and proliferation, lipid metabolism, fibrosis andviral infections.

In some embodiments, the present disclosure provides methods fortreating a subject suffering or at risk of chronic autoimmune andinflammatory conditions by administering to the subject in need thereofan effective amount of a compound of Formulae (I) or (II); or apharmaceutically acceptable salt, a solvate, a tautomer, an isomer, or adeuterated analog of Formulae (I) or (II); or any of the compounds inTable I, or any of the pharmaceutical compositions thereof describedherein. The chronic autoimmune and inflammatory conditions treatablewith the compounds of the present disclosure include, but are notlimited to, rheumatoid arthritis, osteoarthritis, acute gout, psoriasis,systemic lupus erythematosus, multiple sclerosis, inflammatory boweldisease (Crohn's disease and Ulcerative colitis), asthma, chronicobstructive airways disease, pneumonitis, myocarditis, pericarditis,myositis, eczema, dermatitis, alopecia, vitiligo, bullous skin diseases,nephritis, vasculitis, atherosclerosis, Alzheimer's disease, depression,retinitis, uveitis, scleritis, hepatitis, pancreatitis, primary biliarycirrhosis, sclerosing cholangitis, Addison's disease, hypophysitis,thyroiditis, type I diabetes and acute rejection of transplanted organs.In one embodiment, the disease or condition is sepsis, burns,pancreatitis, major trauma, hemorrhage or ischemia. In anotherembodiment, the disease or condition treatable with the compounds of thepresent disclosure includes sepsis, sepsis syndrome, septic shock orendotoxaemia. In another embodiment, the disease or condition treatablewith the compounds of the present disclosure includes acute or chronicpancreatitis. In another embodiment, the disease or condition treatablewith the compounds of the present disclosure includes burns.

In some embodiments, the present disclosure provides methods fortreating a subject suffering or at risk of acute inflammatory conditionsby administering to the subject in need thereof an effective amount of acompound of Formulae (I) or (II); or a pharmaceutically acceptable salt,a solvate, a tautomer, an isomer, or a deuterated analog of Formulae (I)or (II); any of the compounds in Table I, or any of the pharmaceuticalcompositions thereof described herein. The acute inflammatoryconditions, include, but are not limited to, acute gout, giant cellarteritis, nephritis including lupus nephritis, vasculitis with organinvolvement such as glomerulonephritis, vasculitis including giant cellarteritis, Wegener's granulomatosis, Polyarteritis nodosa, Behcet'sdisease, Kawasaki disease, Takayasu's Arteritis, vasculitis with organinvolvement and acute rejection of transplanted organs.

In some embodiments, the present disclosure provides methods fortreating a subject suffering or at risk of autoimmune and inflammatorydiseases or conditions by administering to the subject in need thereofan effective amount of a compound of Formulae (I) or (II); or apharmaceutically acceptable salt, a solvate, a tautomer, an isomer, or adeuterated analog of Formulae (I) or (II); any of the compounds in TableI, or any of the pharmaceutical compositions thereof described herein.The autoimmune and inflammatory diseases or conditions treatable withthe compounds of the present disclosure which involve inflammatoryresponses to infections with bacteria, viruses, such as herpes virus,human papilloma virus, adenovirus and poxvirus and other DNA viruses;fungi, parasites or their toxins, such as sepsis, sepsis syndrome,septic shock, endotoxaemia, systemic inflammatory response syndrome(SIRS), multi-organ dysfunction syndrome, toxic shock syndrome, acutelung injury, ARDS (adult respiratory distress syndrome), acute renalfailure, fulminant hepatitis, burns, acute pancreatitis, post-surgicalsyndromes, sarcoidosis, Herxheimer reactions, encephalitis, myelitis,meningitis, malaria and SIRS associated with viral infections such asinfluenza, herpes zoster, herpes simplex and coronavirus.

In some embodiments, the present disclosure provides methods fortreating a subject suffering or at risk of ischemia-reperfusion injuryby administering to the subject in need thereof an effective amount of acompound of Formulae (I) or (II); or a pharmaceutically acceptable salt,a solvate, a tautomer, an isomer, or a deuterated analog of Formulae (I)or (II); any of the compounds in Table I, or any of the pharmaceuticalcompositions thereof described herein. The ischemia-reperfusion injury,includes, but is not limited to, myocardial infarction, cerebro-vascularischemia (stroke), acute coronary syndromes, renal reperfusion injury,organ transplantation, coronary artery bypass grafting, cardio-pulmonarybypass procedures, pulmonary, renal, hepatic, gastro-intestinal andperipheral limb embolism.

In some embodiments, the present disclosure provides methods fortreating a subject suffering or at risk of hypercholesterolemia,atherosclerosis or Alzheimer's disease by administering to the subjectin need thereof an effective amount of a compound of Formulae (I) or(II); or a pharmaceutically acceptable salt, a solvate, a tautomer, anisomer, or a deuterated analog of Formulae (I) or (II); any of thecompounds in Table I, or any of the pharmaceutical compositions thereofdescribed herein.

In some embodiments, the present disclosure provides methods fortreating any bromodomain mediated disease or condition, including anybromodomain mutant mediated disease or condition in an animal subject inneed thereof, wherein the method involves administering to the subjectan effective amount of any one or more compound(s) as described hereinor any pharmaceutical compositions thereof described herein. In certainembodiments, the method involves administering to the subject aneffective amount of any one or more compound(s) as described herein orany pharmaceutical compositions thereof described herein in combinationwith one or more other therapies or therapeutic agents for the diseaseor condition.

In some embodiments, a compound of Formulae (I) or (II); or apharmaceutically acceptable salt, a solvate, a tautomer, an isomer, or adeuterated analog of Formulae (I) or (II); or any of the compounds inTable I, is a bromodomain inhibitor and has an IC₅₀ of less than 500 nM,less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM,less than 5 nM, or less than 1 nM as determined in a generally acceptedbromodomain activity assay. In some embodiments, a compound as describedherein will have an IC₅₀ of less than 500 nM, less than 100 nM, lessthan 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or lessthan 1 nM with respect to bromodomain, e.g., BET protein, BRD2, BRD3 orBRD4 protein. In some embodiments, a compound as described herein willselectively inhibit one or more bromodomain relative to one or moreother proteins.

In some embodiments, the present disclosure provides a method forinhibiting a bromodomain or mutant bromodomain. The method includescontacting a compound of Formulae (I) or (II); or a pharmaceuticallyacceptable salt, a solvate, a tautomer, an isomer, or a deuteratedanalog of Formulae (I) or (II); any of the compounds in Table I, or anyof the pharmaceutical compositions thereof described herein, with a cellor a bromodomain protein in vitro or in vivo.

In certain embodiments, the present disclosure provides use of acompound of Formulae (I) or (II); or a pharmaceutically acceptable salt,a solvate, a tautomer, an isomer, or a deuterated analog of Formulae (I)or (II); any of the compounds in Table I, or any of the pharmaceuticalcompositions thereof described herein in the manufacture of a medicamentfor the treatment of a disease or condition as described herein. Inother embodiments, the present disclosure provides a compound ofFormulae (I) or (II); or a pharmaceutically acceptable salt, a solvate,a tautomer, an isomer, or a deuterated analog of Formulae (I) or (II);any of the compounds in Table I, or any of the pharmaceuticalcompositions thereof described herein for use in treating a disease orcondition as described herein.

Combination Therapy

Bromodomain modulators may be usefully combined with anotherpharmacologically active compound, or with two or more otherpharmacologically active compounds, particularly in the treatment ofcancer and other diseases and indications described herein. In oneembodiment, the composition includes any one or more compound(s) asdescribed herein along with one or more compounds that aretherapeutically effective for the same disease indication, wherein thecompounds have a synergistic effect on the disease indication. In oneembodiment, the composition includes any one or more compound(s) asdescribed herein effective in treating a cancer and one or more othercompounds that are effective in treating the same cancer, furtherwherein the compounds are synergistically effective in treating thecancer.

In some embodiments, the present disclosure provides methods fortreating a bromodomain or mutant bromodomain mediated disease orcondition in an animal subject in need thereof, wherein the methodinvolves administering to the subject an effective amount of any one ormore compound(s) as described herein, or one or more compounds ofFormulae (I) or (II); or a pharmaceutically acceptable salt, a solvate,a tautomer, an isomer, or a deuterated analog of Formulae (I) or (II);any of the compounds in Table I, or any of the pharmaceuticalcompositions thereof described herein, in combination with one or moreother therapeutic agent as described herein. In certain embodiments, thepresent disclosure provides methods for treating bromodomain or mutantbromodomain mediated disease or condition in an animal subject in needthereof, wherein the method involves administering to the subject aneffective amount of any one or more compound(s) of Formulae (I) or (II);or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer,or a deuterated analog of Formulae (I) or (II); any of the compounds inTable I, or any of the pharmaceutical compositions thereof describedherein, in combination with one or more other therapies for the diseaseor condition.

In some embodiments, the present disclosure provides a composition,e.g., a pharmaceutical composition comprising a compound of Formulae (I)or (II); or a pharmaceutically acceptable salt, a solvate, a tautomer,an isomer, or a deuterated analog of Formulae (I) or (II); any of thecompounds in Table I, or any of the pharmaceutical compositions thereofdescribed herein, and one or more other therapeutic agents. In someembodiments, the one or more other therapeutic agents are selected froman alkylating agent, including, but not limiting to, adozelesin,altretamine, bendamustine, bizelesin, busulfan, carboplatin, carboquone,carmofur, carmustine, chlorambucil, cisplatin, cyclophosphamide,dacarbazine, estramustine, etoglucid, fotemustine, hepsulfam,ifosfamide, improsulfan, irofulven, lomustine, mannosulfan,mechlorethamine, melphalan, mitobronitol, nedaplatin, nimustine,oxaliplatin, piposulfan, prednimustine, procarbazine, ranimustine,satraplatin, semustine, streptozocin, temozolomide, thiotepa,treosulfan, triaziquone, triethylenemelamine, triplatin tetranitrate,trofosphamide, and uramustine; an antibiotic, including, but notlimiting to, aclarubicin, amrubicin, bleomycin, dactinomycin,daunorubicin, doxorubicin, elsamitrucin, epirubicin, idarubicin,menogaril, mitomycin, neocarzinostatin, pentostatin, pirarubicin,plicamycin, valrubicin, and zorubicin; an antimetabolite, including, butnot limiting to, aminopterin, azacitidine, azathioprine, capecitabine,cladribine, clofarabine, cytarabine, decitabine, floxuridine,fludarabine, 5-fluorouracil, gemcitabine, hydroxyurea, mercaptopurine,methotrexate, nelarabine, pemetrexed, raltitrexed, tegafur-uracil,thioguanine, trimethoprim, trimetrexate, and vidarabine; animmunotherapy, an antibody therapy, including, but not limiting to,alemtuzumab, bevacizumab, cetuximab, galiximab, gemtuzumab, panitumumab,pertuzumab, rituximab, brentuximab, tositumomab, trastuzumab, 90 Yibritumomab tiuxetan, ipilimumab, tremelimumab and anti-CTLA-4antibodies; a hormone or hormone antagonist, including, but not limitingto, anastrozole, androgens, buserelin, diethylstilbestrol, exemestane,flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprolide,magestrol, raloxifene, tamoxifen, and toremifene; a taxane, including,but not limiting to, DJ-927, docetaxel, TPI 287, larotaxel, ortataxel,paclitaxel, DHA-paclitaxel, and tesetaxel; a retinoid, including, butnot limiting to, alitretinoin, bexarotene, fenretinide, isotretinoin,and tretinoin; an alkaloid, including, but not limiting to, demecolcine,homoharringtonine, vinblastine, vincristine, vindesine, vinflunine, andvinorelbine; an antiangiogenic agent, including, but not limiting to,AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenalidomide,and thalidomide; a topoisomerase inhibitor, including, but not limitingto, amsacrine, belotecan, edotecarin, etoposide, etoposide phosphate,exatecan, irinotecan (also active metabolite SN-38(7-ethyl-10-hydroxy-camptothecin)), lucanthone, mitoxantrone,pixantrone, rubitecan, teniposide, topotecan, and 9-aminocamptothecin; akinase inhibitor, including, but not liming to, axitinib (AG 013736),dasatinib (BMS 354825), erlotinib, gefitinib, flavopiridol, imatinibmesylate, lapatinib, motesanib diphosphate (AMG 706), nilotinib(AMN107), seliciclib, sorafenib, sunitinib malate, AEE-788, BMS-599626,UCN-01 (7-hydroxystaurosporine), vemurafenib, dabrafenib, selumetinib,LGX818, BGB-283, pexidartinib (PLX3397) and vatalanib; a targeted signaltransduction inhibitor including, but not limiting to bortezomib,geldanamycin, and rapamycin; a biological response modifier, including,but not limiting to, imiquimod, interferon-α, and interleukin-2; andother chemotherapeutics, including, but not limiting to 3-AP(3-amino-2-carboxyaldehyde thiosemicarbazone), altrasentan,aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide,elesclomol, eribulin mesylate (E7389), ixabepilone, lonidamine,masoprocol, mitoguanazone, oblimersen, sulindac, testolactone,tiazofurin, mTOR inhibitors (e.g. sirolimus, temsirolimus, everolimus,deforolimus), PI3K inhibitors (e.g. BEZ235, GDC-0941, XL147, XL765,•BMK120), Cdk4 inhibitors (e.g. PD-332991), Akt inhibitors, Hsp90inhibitors (e.g. geldanamycin, radicicol, tanespimycin),farnesyltransferase inhibitors (e.g. tipifarnib), and Aromataseinhibitors (anastrozole letrozole exemestane). In one embodiment, themethod of treating a cancer involves administering to the subject aneffective amount of a composition including any one or more compound(s)of Formulae (I) or (II); or a pharmaceutically acceptable salt, asolvate, a tautomer, an isomer, or a deuterated analog of Formulae (I)or (II); or any of the compounds in Table I, in combination with achemotherapeutic agent selected from capecitabine, 5-fluorouracil,carboplatin, dacarbazine, gefitinib, oxaliplatin, paclitaxel, SN-38,temozolomide, vinblastine, bevacizumab, cetuximab, interferon-α,interleukin-2, or erlotinib. In another embodiment, the chemotherapeuticagent is a Mek inhibitor. Exemplary Mek inhibitors include, but are notlimited to, AS703026, AZD6244 (Selumetinib), AZD8330, BIX 02188, CI-1040(PD184352), GSK1120212 (JTP-74057), PD0325901, PD318088, PD98059,RDEA119(BAY 869766), TAK-733 and U0126-EtOH. In another embodiment, thechemotherapeutic agent is a tyrosine kinase inhibitor. Exemplarytyrosine kinase inhibitors include, but are not limited to, AEE788,AG-1478 (Tyrphostin AG-1478), AG-490, Apatinib (YN968D1), AV-412,AV-951(Tivozanib), Axitinib, AZD8931, BIBF1120 (Vargatef), BIBW2992(Afatinib), BMS794833, BMS-599626, Brivanib (BMS-540215), Brivanibalaninate(BMS-582664), Cediranib (AZD2171), Chrysophanic acid(Chrysophanol), Crenolanib (CP-868569), CUDC-101, CYC116, DovitinibDilactic acid (TKI258 Dilactic acid), E7080, Erlotinib Hydrochloride(Tarceva, CP-358774, OSI-774, NSC-718781), Foretinib (GSK1363089,XL880), Gefitinib (ZD-1839 or Iressa), Imatinib (Gleevec), ImatinibMesylate, Ki8751, KRN 633, Lapatinib (Tykerb), Linifanib (ABT-869),Masitinib (Masivet, AB1010), MGCD-265, Motesanib (AMG-706), MP-470,Mubritinib (TAK 165), Neratinib (HKI-272), NVP-BHG712, OSI-420(Desmethyl Erlotinib,CP-473420), OSI-930, Pazopanib HCl, PD-153035 HCl,PD173074, Pelitinib (EKB-569), PF299804, Ponatinib (AP24534), PP121,RAF265 (CHIR-265), Raf265 derivative, Regorafenib (BAY 73-4506),Sorafenib Tosylate (Nexavar), Sunitinib Malate (Sutent), Telatinib (BAY57-9352), TSU-68 (SU6668), Vandetanib (Zactima), Vatalanibdihydrochloride (PTK787), WZ3146, WZ4002, WZ8040, quizartinib,Cabozantinib, XL647, EGFR siRNA, FLT4 siRNA, KDR siRNA, Antidiabeticagents such as metformin, PPAR agonists (rosiglitazone, pioglitazone,bezafibrate, ciprofibrate, clofibrate, gemfibrozil, fenofibrate,indeglitazar), and DPP4 inhibitors (sitagliptin, vildagliptin,saxagliptin, dutogliptin, gemigliptin, alogliptin). In anotherembodiment, the agent is an EGFR inhibitor. Exemplary EGFR inhibitorsinclude, but are not limited to, AEE-788, AP-26113, BIBW-2992 (Tovok),CI-1033, GW-572016, Iressa, LY2874455, RO-5323441, Tarceva (Erlotinib,OSI-774), CUDC-101 and WZ4002. In another embodiment, the therapeuticagent for combination is a c-Fms and/or c-Kit inhibitor as described inUS Patent Application Publication Nos. 2009/0076046 and 2011/0112127,which are incorporated herein by reference in their entirety and for allpurposes. In one embodiment, the method of treating a cancer involvesadministering to the subject an effective amount of a compositionincluding any one or more compound(s) as described herein in combinationwith a chemotherapeutic agent selected from capecitabine,5-fluorouracil, carboplatin, dacarbazine, gefitinib, oxaliplatin,paclitaxel, SN-38, temozolomide, vinblastine, bevacizumab, cetuximab,interferon-α, interleukin-2, or erlotinib. In some embodiments, abromodomain modulator, particularly a compound of any of Formulae (I) or(II); or a pharmaceutically acceptable salt, a solvate, a tautomer, anisomer, or a deuterated analog of Formulae (I) or (II); or any of thecompounds in Table I, may be administered simultaneously, sequentiallyor separately in combination with one or more agents as described above.

In some embodiments, the present disclosure provides a composition,e.g., a pharmaceutical composition comprising a compound of Formulae (I)or (II); or a pharmaceutically acceptable salt, a solvate, a tautomer,an isomer, or a deuterated analog of Formulae (I) or (II); any of thecompounds in Table I, or any of the pharmaceutical compositions thereofdescribed herein, and one or more other therapeutic agents. In someembodiments, the one or more other therapeutic agents are selected froman alkylating agent, including, but not limiting to, adozelesin,altretamine, bendamustine, bizelesin, busulfan, carboplatin, carboquone,carmofur, carmustine, chlorambucil, cisplatin, cyclophosphamide,dacarbazine, estramustine, etoglucid, fotemustine, hepsulfam,ifosfamide, improsulfan, irofulven, lomustine, mannosulfan,mechlorethamine, melphalan, mitobronitol, nedaplatin, nimustine,oxaliplatin, piposulfan, prednimustine, procarbazine, ranimustine,satraplatin, semustine, streptozocin, temozolomide, thiotepa,treosulfan, triaziquone, triethylenemelamine, triplatin tetranitrate,trofosphamide, and uramustine; an antibiotic, including, but notlimiting to, aclarubicin, amrubicin, bleomycin, dactinomycin,daunorubicin, doxorubicin, elsamitrucin, epirubicin, idarubicin,menogaril, mitomycin, neocarzinostatin, pentostatin, pirarubicin,plicamycin, valrubicin, and zorubicin; an antimetabolite, including, butnot limiting to, aminopterin, azacitidine, azathioprine, capecitabine,cladribine, clofarabine, cytarabine, decitabine, floxuridine,fludarabine, 5-fluorouracil, gemcitabine, hydroxyurea, mercaptopurine,methotrexate, nelarabine, pemetrexed, raltitrexed, tegafur-uracil,thioguanine, trimethoprim, trimetrexate, and vidarabine; animmunotherapy, an antibody therapy, including, but not limiting to,alemtuzumab, bevacizumab, cetuximab, galiximab, gemtuzumab, panitumumab,pertuzumab, rituximab, brentuximab, tositumomab, trastuzumab, 90 Yibritumomab tiuxetan, ipilimumab, tremelimumab and anti-CTLA-4antibodies; a hormone or hormone antagonist, including, but not limitingto, anastrozole, androgens, buserelin, diethylstilbestrol, exemestane,flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprolide,magestrol, raloxifene, tamoxifen, and toremifene; a taxane, including,but not limiting to, DJ-927, docetaxel, TPI 287, larotaxel, ortataxel,paclitaxel, DHA-paclitaxel, and tesetaxel; a retinoid, including, butnot limiting to, alitretinoin, bexarotene, fenretinide, isotretinoin,and tretinoin; an alkaloid, including, but not limiting to, demecolcine,homoharringtonine, vinblastine, vincristine, vindesine, vinflunine, andvinorelbine; an antiangiogenic agent, including, but not limiting to,AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenalidomide,and thalidomide; a topoisomerase inhibitor, including, but not limitingto, amsacrine, belotecan, edotecarin, etoposide, etoposide phosphate,exatecan, irinotecan (also active metabolite SN-38(7-ethyl-10-hydroxy-camptothecin)), lucanthone, mitoxantrone,pixantrone, rubitecan, teniposide, topotecan, and 9-aminocamptothecin; akinase inhibitor, including, but not liming to, axitinib (AG 013736),dasatinib (BMS 354825), erlotinib, gefitinib, flavopiridol, imatinibmesylate, lapatinib, motesanib diphosphate (AMG 706), nilotinib(AMN107), seliciclib, sorafenib, sunitinib malate, AEE-788, BMS-599626,UCN-01 (7-hydroxystaurosporine), vemurafenib, dabrafenib, selumetinib,paradox breakers (such as PLX8394 or PLX7904), LGX818, BGB-283,pexidartinib (PLX3397) and vatalanib; a targeted signal transductioninhibitor including, but not limiting to bortezomib, geldanamycin, andrapamycin; a biological response modifier, including, but not limitingto, imiquimod, interferon-α, and interleukin-2; and otherchemotherapeutics, including, but not limiting to 3-AP(3-amino-2-carboxyaldehyde thiosemicarbazone), altrasentan,aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide,elesclomol, eribulin mesylate (E7389), ixabepilone, lonidamine,masoprocol, mitoguanazone, oblimersen, sulindac, testolactone,tiazofurin, mTOR inhibitors (e.g. sirolimus, temsirolimus, everolimus,deforolimus, INK28, AZD8055, PI3K inhibitors (e.g. BEZ235, GDC-0941,XL147, XL765, BMK120), Cdk4 inhibitors (e.g. PD-332991), Akt inhibitors,Hsp90 inhibitors (e.g. geldanamycin, radicicol, tanespimycin),farnesyltransferase inhibitors (e.g. tipifarnib), and Aromataseinhibitors (anastrozole letrozole exemestane). In one embodiment, themethod of treating a cancer involves administering to the subject aneffective amount of a composition including any one or more compound(s)of Formulae (I) or (II); or a pharmaceutically acceptable salt, asolvate, a tautomer, an isomer, or a deuterated analog of Formulae (I)or (II); or any of the compounds in Table I, in combination with achemotherapeutic agent selected from capecitabine, 5-fluorouracil,carboplatin, dacarbazine, gefitinib, oxaliplatin, paclitaxel, SN-38,temozolomide, vinblastine, bevacizumab, cetuximab, interferon-α,interleukin-2, or erlotinib. In another embodiment, the chemotherapeuticagent is a Mek inhibitor. Exemplary Mek inhibitors include, but are notlimited to, AS703026, AZD6244 (Selumetinib), AZD8330, BIX 02188, CI-1040(PD184352), GSK1120212 (also known as trametinib or JTP-74057),cobimetinib, PD0325901, PD318088, PD98059, RDEA119(BAY 869766), TAK-733and U0126-EtOH. In another embodiment, the chemotherapeutic agent is atyrosine kinase inhibitor. Exemplary tyrosine kinase inhibitors include,but are not limited to, AEE788, AG-1478 (Tyrphostin AG-1478), AG-490,Apatinib (YN968D1), AV-412, AV-951(Tivozanib), Axitinib, AZD8931,BIBF1120 (Vargatef), BIBW2992 (Afatinib), BMS794833, BMS-599626,Brivanib (BMS-540215), Brivanib alaninate(BMS-582664), Cediranib(AZD2171), Chrysophanic acid (Chrysophanol), Crenolanib (CP-868569),CUDC-101, CYC116, Dovitinib Dilactic acid (TKI258 Dilactic acid), E7080,Erlotinib Hydrochloride (Tarceva, CP-358774, OSI-774, NSC-718781),Foretinib (GSK1363089, XL880), Gefitinib (ZD-1839 or Iressa), Imatinib(Gleevec), Imatinib Mesylate, Ki8751, KRN 633, Lapatinib (Tykerb),Linifanib (ABT-869), Masitinib (Masivet, AB1010), MGCD-265, Motesanib(AMG-706), MP-470, Mubritinib(TAK 165), Neratinib (HKI-272), NVP-BHG712,OSI-420 (Desmethyl Erlotinib,CP-473420), OSI-930, Pazopanib HCl,PD-153035 HCl, PD173074, Pelitinib (EKB-569), PF299804, Ponatinib(AP24534), PP121, RAF265 (CHIR-265), Raf265 derivative, Regorafenib (BAY73-4506), Sorafenib Tosylate (Nexavar), Sunitinib Malate (Sutent),Telatinib (BAY 57-9352), TSU-68 (SU6668), Vandetanib (Zactima),Vatalanib dihydrochloride (PTK787), WZ3146, WZ4002, WZ8040, quizartinib,Cabozantinib, XL647, EGFR siRNA, FLT4 siRNA, KDR siRNA, Antidiabeticagents such as metformin, PPAR agonists (rosiglitazone, pioglitazone,bezafibrate, ciprofibrate, clofibrate, gemfibrozil, fenofibrate,indeglitazar), and DPP4 inhibitors (sitagliptin, vildagliptin,saxagliptin, dutogliptin, gemigliptin, alogliptin). In anotherembodiment, the agent is an EGFR inhibitor. Exemplary EGFR inhibitorsinclude, but are not limited to, AEE-788, AP-26113, BIBW-2992 (Tovok),CI-1033, GW-572016, Iressa, LY2874455, RO-5323441, Tarceva (Erlotinib,OSI-774), CUDC-101 and WZ4002. In another embodiment, the therapeuticagent for combination is a c-Fms and/or c-Kit inhibitor as described inUS Patent Application Publication Nos. 2009/0076046 and 2011/0112127,which are incorporated herein by reference in their entirety and for allpurposes. In one embodiment, the method of treating a cancer involvesadministering to the subject an effective amount of a compositionincluding any one or more compound(s) as described herein in combinationwith a chemotherapeutic agent selected from capecitabine,5-fluorouracil, carboplatin, dacarbazine, gefitinib, oxaliplatin,paclitaxel, SN-38, temozolomide, vinblastine, bevacizumab, cetuximab,interferon-α, interleukin-2, or erlotinib. In some embodiments, abromodomain modulator, particularly a compound of any of Formulae (I) or(II); or a pharmaceutically acceptable salt, a solvate, a tautomer, anisomer, or a deuterated analog of Formulae (I) or (II); or any of thecompounds in Table I, may be administered simultaneously, sequentiallyor separately in combination with one or more agents as described above.

In another embodiment, the present disclosure provides a composition,e.g., a pharmaceutical composition comprising a compound of Formulae (I)or (II); or a pharmaceutically acceptable salt, a solvate, a tautomer,an isomer, or a deuterated analog of Formulae (I) or (II); any of thecompounds in Table I, or any of the pharmaceutical compositions thereofdescribed herein, and one or more other therapeutic agents selected fromthe group consisting of i) an alkylating agent selected from adozelesin,altretamine, bizelesin, busulfan, carboplatin, carboquone, carmustine,chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine,fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven, lomustine,mechlorethamine, melphalan, oxaliplatin, piposulfan, semustine,streptozocin, temozolomide, thiotepa, and treosulfan; ii) an antibioticselected from bleomycin, dactinomycin, daunorubicin, doxorubicin,epirubicin, idarubicin, menogaril, mitomycin, mitoxantrone,neocarzinostatin, pentostatin, and plicamycin; iii) an antimetaboliteselected from the group consisting of azacitidine, capecitabine,cladribine, clofarabine, cytarabine, decitabine, floxuridine,fludarabine, 5-fluorouracil, ftorafur, gemcitabine, hydroxyurea,mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed,thioguanine, and trimetrexate; iv) an antibody therapy agent selectedfrom alemtuzumab, bevacizumab, cetuximab, galiximab, gemtuzumab,nivolumab, panitumumab, pembrolizumab, pertuzumab, rituximab,tositumomab, trastuzumab, and 90 Y ibritumomab tiuxetan; v) a hormone orhormone antagonist selected from the group consisting of anastrozole,androgens, buserelin, diethylstilbestrol, exemestane, flutamide,fulvestrant, goserelin, idoxifene, letrozole, leuprolide, magestrol,raloxifene, tamoxifen, and toremifene; vi) a taxane selected fromDJ-927, docetaxel, TPI 287, paclitaxel and DHA-paclitaxel; vii) aretinoid selected from alitretinoin, bexarotene, fenretinide,isotretinoin, and tretinoin; viii) an alkaloid selected from etoposide,homoharringtonine, teniposide, vinblastine, vincristine, vindesine, andvinorelbine; ix) an antiangiogenic agent selected from AE-941 (GW786034,Neovastat), ABT-510, 2-methoxyestradiol, lenalidomide, and thalidomide;x) a topoisomerase inhibitor selected from amsacrine, edotecarin,exatecan, irinotecan, SN-38 (7-ethyl-10-hydroxy-camptothecin),rubitecan, topotecan, and 9-aminocamptothecin; xi) a kinase inhibitorselected from erlotinib, gefitinib, flavopiridol, imatinib mesylate,lapatinib, sorafenib, sunitinib malate, AEE-788, AG-013736, AMG 706,AMN107, BMS-354825, BMS-599626, UCN-01 (7-hydroxystaurosporine),vemurafenib, dabrafenib, trametinib, cobimetinib selumetinib andvatalanib; xii) a targeted signal transduction inhibitor selected frombortezomib, geldanamycin, and rapamycin; xiii) a biological responsemodifier selected from imiquimod, interferon-α and interleukin-2; xiv)an IDO inhibitor; and xv) a chemotherapeutic agent selected from 3-AP(3-amino-2-carboxyaldehyde thiosemicarbazone), altrasentan,aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide,elesclomol, eribulin mesylate (E7389), ixabepilone, lonidamine,masoprocol, mitoguanazone, oblimersen, sulindac, testolactone,tiazofurin, a mTOR inhibitor, a PI3K inhibitor, a Cdk4 inhibitor, an Aktinhibitor, a Hsp90 inhibitor, a farnesyltransferase inhibitor or anaromatase inhibitor (anastrozole letrozole exemestane); xvi) a Mekinhibitor; xvii) a tyrosine kinase inhibitor; xviii) a c-Kit mutantinhibitor, xix) an EGFR inhibitor, or xx) an epigenetic modulator. Infurther embodiments, a bromodomain modulator, particularly a compound ofany of Formulae (I) or (II); or a pharmaceutically acceptable salt, asolvate, a tautomer, an isomer, or a deuterated analog of Formulae (I)or (II); or any of the compounds in Table I, may be administeredsimultaneously, sequentially or separately in combination with one ormore agents as described above.

Epigenetic modulators include DNA methylating agents and agents thatmodulate posttranslational modification of histones and/or proteins bythe activity of chromatin modifiers. Non-limiting examples of Epigeneticmodulators include:

(a) DNA methyltransferases (for example, azacytidine, decitabine orzebularine);

(b) histone and protein methyltransferases, including, but not limitedto, DOT1L inhibitors such as EPZ004777(7-[5-Deoxy-5-[[3-[[[[4-(1,1-dimethylethyl)phenyl]amino]carbonyl]amino]propyl](1-methylethyl)amino]-β-D-ribofuranosyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine),EZH1 inhibitors, EZH2 inhibitors or EPX5687;

(c) histone demethylases;

(d) histone deacetylase inhibitors (HDAC inhibitors) including, but notlimited to, vorinostat, romidepsin, chidamide, panobinostat, belinostat,valproic acid, mocetinostat, abexinostat, entinostat, resminostat,givinostat, or quisinostat;

(e) histone acetyltransferase inhibitors (also referred to as HATinhibitors) including, but not limited to, C-646,(4-[4-[[5-(4,5-Dimethyl-2-nitrophenyl)-2-furanyl]methylene]-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl]benzoicacida), CPTH2(cyclopentylidene-[4-(4′-chlorophenyl)thiazol-2-yl]hydrazine), CTPB(N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-6-pentadecyl-benzamide),garcinol((1R,5R,7R)-3-(3,4-Dihydroxybenzyol)-4-hydroxy-8,8-dimethyl-1,7-bis(3-methyl-2-buten-1-yl)-5-[(2S)-5-methyl-2-(1-methylethenyl)-4-hexen-1-yl]bicyclo[3.3.1]non-3-ene-2,9-dione),anacardic acid, EML 425(5-[(4-hydroxy-2,6-dimethylphenyl)methylene]-1,3-bis(phenylmethyl)-2,4,6(1H,3H,5H)-pyrimidinetrione),ISOX DUAL([3-[4-[2-[5-(Dimethyl-1,2-oxazol-4-yl)-1-[2-(morpholin-4-yl)ethyl]-1H-1,3-benzodiazol-2-yl]ethyl]phenoxy]propyl]dimethylamine),L002(4-[O-[(4-methoxyphenyl)sulfonyl]oxime]-2,6-dimethyl-2,5-cyclohexadiene-1,4-dione),NU 9056 (5-(1,2-thiazol-5-yldisulfanyl)-1,2-thiazole), SI-2hydrochloride (1-(2-pyridinyl)ethanone2-(1-methyl-1H-benzimidazol-2-yl)hydrazone hydrochloride); or

(f) other chromatin remodelers.

In another embodiment, the epigenetic modulator is vorinostat,romidepsin, belinostat, or panobinostat.

In some embodiments, the present disclosure provides methods fortreating a disease or condition mediated by bromodomain, including anymutations thereof, by administering to a subject an effective amount ofa composition as described herein, which includes any one or morecompound(s) as described herein in combination with one or more othertherapeutic agents as described herein. In other embodiments, thepresent disclosure provides methods for treating a disease or conditionmediated by bromodomain protein or mutant bromodomain protein, includingany mutations thereof, by administering to a subject an effective amountof a composition as described herein, which includes any one or morecompound(s) as described herein in combination with one or more othersuitable therapies for treating the disease or condition. In oneembodiment, the present disclosure provides methods for treating acancer mediated by bromodomain or mutant bromodomain by administering tothe subject an effective amount of a composition including any one ormore compound(s) as described herein. In one embodiment, the presentdisclosure provides methods for treating a cancer mediated bybromodomain by administering to the subject an effective amount of acomposition including any one or more compound(s) as described herein incombination with one or more suitable anticancer therapies, such as oneor more chemotherapeutic drugs or agents as described herein.

In some embodiments, compositions are provided that include atherapeutically effective amount of any one or more compound(s) asdescribed herein and at least one pharmaceutically acceptable carrier,excipient, and/or diluent, including combinations of any two or morecompounds as described herein. The composition can further include aplurality of different pharmacologically active compounds, which caninclude a plurality of compounds as described herein. In certainembodiments, the composition can include any one or more compound(s) asdescribed herein along with one or more compounds that aretherapeutically effective for the same disease indication. In oneaspect, the composition includes any one or more compound(s) asdescribed herein along with one or more compounds that aretherapeutically effective for the same disease indication, wherein thecompounds have a synergistic effect on the disease indication. In oneembodiment, the composition includes any one or more compound(s) asdescribed herein effective in treating a cancer and one or more othercompounds that are effective in treating the same cancer, furtherwherein the compounds are synergistically effective in treating thecancer. The compounds can be administered simultaneously orsequentially.

In some embodiments, the present disclosure provides a composition,e.g., a pharmaceutical composition comprising a compound of Formulae (I)or (II), any of the compounds in Table I, or a pharmaceuticallyacceptable salt, a solvate, a tautomer, an isomer, or a deuteratedanalog of Formulae (I) or (II); or any of the compounds in Table I, incombination with a FMS inhibitor, such as quizartinib or pexidartinib.

In one embodiment, the present disclosure provides methods for treatinga disease or condition mediated by bromodomain or mutant bromodomainprotein, by administering to the subject an effective amount a compoundof Formulae (I) or (II), any of the compounds in Table I, or apharmaceutically acceptable salt, a solvate, a tautomer, an isomer, or adeuterated analog of Formulae (I) or (II); or any of the compounds inTable I, in combination quizartinib for treating the disease orcondition.

In some embodiments, the disclosure provides a method of treating asubject suffering from a disease or condition described in thisdisclosure, said method comprising administering to the subject aneffective amount of Formulae (I) or (II), any of the compounds in TableI, or a pharmaceutically acceptable salt, a solvate, a tautomer, anisomer, or a deuterated analog of Formulae (I) or (II); or any of thecompounds in Table I, in combination with a mutant c-Kit protein kinaseinhibitor. In another embodiment, the mutant c-Kit protein kinaseinhibitor is selected from(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-(3-pyridyl)methanol,(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-(3-pyridyl)methanone,N-(3-carbamoylphenyl)-2-phenyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide,2-phenyl-N-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide,4-bromo-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide,ethyl3-[(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbamoylamino]propanoate,3,4-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide,4-methyl-3-phenyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide,3-cyclopropyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide,5-fluoro-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-indazole-3-carboxamide,N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidine-4-carboxamide,3-fluoro-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridine-2-carboxamide,3,5-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isoxazole-4-carboxamide,N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridazine-3-carboxamide,N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2H-triazole-4-carboxamide,3-methyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridine-2-carboxamide,4,5-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isoxazole-3-carboxamideor N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-4-sulfonamide.In another embodiment, the compound of Formulae (I) or (II), any of thecompounds in Table I, or a pharmaceutically acceptable salt, a solvate,a tautomer, an isomer, or a deuterated analog of Formulae (I) or (II);or any of the compounds in Table I, is combined with any of the mutantc-Kit mutant inhibitiors described in this specification for treatingGIST—which includes, without limitation, 1^(st) line, 2^(nd) line andneoadjuvant GIST.

In some embodiments, the present disclosure provides a composition,e.g., a pharmaceutical composition comprising at least onepharmaceutically acceptable carrier or excipient and any of one of thecompounds in Table II, or a pharmaceutically acceptable salt, a solvate,a tautomer, an isomer, or a deuterated analog of any of the compounds inTable II in combination with a FMS inhibitor, such as quizartinib orpexidartinib. In some embodiments, the present disclosure provides apharmaceutical composition comprising: any of one of the compounds inTable II, or a pharmaceutically acceptable salt, a solvate, a tautomer,an isomer, or a deuterated analog of any of the compounds in Table II; apharmaceutically acceptable carrier; and quizartinib.

In some embodiments, the present disclosure provides methods fortreating a subject suffering or at risk of a disease or conditionmediated by a bromodomain, said method comprising administering to thesubject in need thereof an effective amount of any of the compoundsaccording to Table II or a pharmaceutically acceptable salt, a solvate,a tautomer, an isomer, or a deuterated analog of any of one thecompounds in Table II, or a composition comprising any of the compoundsin Table II or a pharmaceutically acceptable salt, a solvate, atautomer, an isomer, or a deuterated analog of any of one the compoundsin Table II, and a pharmaceutical acceptable excipient or carrier incombination with quizartinib.

In some embodiments, the present disclosure provides methods fortreating a subject suffering or at risk of a disease or conditionmediated by a bromodomain, said method comprising administering to thesubject in need thereof an effective amount of a pharmaceuticalcomposition comprising: any of one of the compounds in Table II, or apharmaceutically acceptable salt, a solvate, a tautomer, an isomer, or adeuterated analog of any of the compounds in Table II; at least onepharmaceutically acceptable excipient or carrier; and quizartinib

TABLE II3,5-dimethyl-4-[1-(1-phenylethyl)-3-(1,3,5-trimethylpyrazol-4-yl)pyrrolo[3,2-b]pyridin-6-yl]isoxazole3,5-dimethyl-4-[3-oxazol-5-yl-1-(1-phenylethyl)pyrrolo[3,2-b]pyridin-6-yl]isoxazole3-[6-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)pyrrolo[3,2-b]pyridin-3-yl]prop-2-yn-1-ol4-[1-[(3,3-difluorocyclobutyl)methyl]-3-iodo-pyrrolo[3,2-b]pyridin-6-yl]-3,5-dimethyl-isoxazole4-[1-[(3,3-difluorocyclobutyl)methyl]-3-[1-(difluoromethyl)pyrazol-4-yl]pyrrolo[3,2-b]pyridin-6-yl]-3,5-dimethyl-isoxazole4-[1-[(3,3-difluorocyclobutyl)methyl]-3-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyrrolo[3,2-b]pyridin-6-yl]-3,5-dimethyl-isoxazole4-[3-chloro-1-[(4,4-difluorocyclohexyl)methyl]pyrrolo[3,2-b]pyridin-6-yl]-3,5-dimethyl-isoxazole3-[3-chloro-6-(3,5-dimethylisoxazol-4-yl)pyrrolo[3,2-b]pyridin-1-yl]-3-cyclopropyl-propanenitrile3-[3-bromo-6-(3,5-dimethylisoxazol-4-yl)pyrrolo[3,2-b]pyridin-1-yl]-3-cyclopropyl-propanenitrile3-cyclopropyl-3-[6-(3,5-dimethylisoxazol-4-yl)-3-iodo-pyrrolo[3,2-b]pyridin-1-yl]propanenitrile1-[(4,4-difluorocyclohexyl)methyl]-6-(3,5-dimethyltriazol-4-yl)-3-(1-methylpyrazol-4-yl)pyrrolo[3,2-b]pyridine1-[(4,4-difluorocyclohexyl)methyl]-6-(3,5-dimethyltriazol-4-yl)-3-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyrrolo[3,2-b]pyridine1-[(4,4-difluorocyclohexyl)methyl]-6-(6-methoxy-3-pyridyl)pyrrolo[3,2-b]pyridine1-[(4,4-difluorocyclohexyl)methyl]-6-(6-methyl-3-pyridyl)pyrrolo[3,2-b]pyridine3-[3-[1-(difluoromethyl)pyrazol-4-yl]-6-(3,5-dimethylisoxazol-4-yl)pyrrolo[3,2-b]pyridin-1-yl]-3-tetrahydropyran-4-yl-propanenitrile3-cyclopropyl-3-[6-(3,5-dimethylisoxazol-4-yl)-3-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyrrolo[3,2-b]pyridin-1-yl]propanenitrile3-cyclopropyl-3-[6-(3,5-dimethylisoxazol-4-yl)-3-(1-methylpyrazol-4-yl)pyrrolo[3,2-b]pyridin-1-yl]propanenitrile4-[1-benzyl-3-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyrrolo[3,2-b]pyridin-6-yl]-3,5-dimethyl-isoxazole4-(1-benzyl-3-iodo-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethyl-isoxazole4-[3-iodo-1-(pyrimidin-2-ylmethyl)pyrrolo[3,2-b]pyridin-6-yl]-3,5-dimethyl-isoxazole3,5-dimethyl-4-[1-[1-(2-pyridyl)ethyl]-3-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyrrolo[3,2-b]pyridin-6-yl]isoxazole3,5-dimethyl-4-[1-[(1,4,4-trifluorocyclohexyl)methyl]-3-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyrrolo[3,2-b]pyridin-6-yl]isoxazole5-[3-(chloromethyl)-5-methyl-1,2,4-triazol-4-yl]-1H-pyrrolo[2,3-b]pyridinetert-butylN-[4-[1-[(4,4-difluorocyclohexyl)methyl]pyrrolo[3,2-b]pyridin-6-yl]-5-methyl-isoxazol-3-yl]carbamate4-[1-[(4,4-difluorocyclohexyl)methyl]-6-(3,5-dimethylisoxazol-4-yl)pyrrolo[3,2-b]pyridin-3-yl]benzoic acid3,5-dimethyl-4-[3-(1-methylpyrazol-4-yl)-1-(pyrimidin-2-ylmethyl)pyrrolo[3,2-b]pyridin-6-yl]isoxazole4-[1-benzyl-3-[1-(difluoromethyl)pyrazol-4-yl]pyrrolo[3,2-b]pyridin-6-yl]-3,5-dimethyl-isoxazole4-[1-benzyl-3-(1-methylpyrazol-4-yl)pyrrolo[3,2-b]pyridin-6-yl]-3,5-dimethyl-isoxazole4-[1-[(4,4-difluorocyclohexyl)methyl]pyrrolo[3,2-b]pyridin-6-yl]-3-methyl-isoxazol-5-amine4-[1-[(4,4-difluorocyclohexyl)methyl]pyrrolo[3,2-b]pyridin-6-yl]-5-methyl-isoxazol-3-aminemethyl4-[1-[(4,4-difluorocyclohexyl)methyl]-6-(3,5-dimethylisoxazol-4-yl)pyrrolo[3,2-b]pyridin-3-yl]benzoate3-[6-(3,5-dimethylisoxazol-4-yl)-3-(1-methylpyrazol-4-yl)pyrrolo[3,2-b]pyridin-1-yl]-3-phenyl-propanenitrile3-[6-(3,5-dimethylisoxazol-4-yl)-3-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyrrolo[3,2-b]pyridin-1-yl]-3-phenyl-propanenitrile4-[3-iodo-1-(2-pyridylmethyl)pyrrolo[3,2-b]pyridin-6-yl]-3,5-dimethyl-isoxazole4-[1-[dideuterio-(4,4-difluorocyclohexyl)methyl]-3-oxazol-5-yl-pyrrolo[3,2-b]pyridin-6-yl]-3,5-dimethyl-isoxazole4-[1-[dideuterio-(4,4-difluorocyclohexyl)methyl]-3-(1,3-dimethylpyrazol-4-yl)pyrrolo[3,2-b]pyridin-6-yl]-3,5-dimethyl-isoxazole4-[1-[dideuterio-(4,4-difluorocyclohexyl)methyl]-3-(1-ethylpyrazol-4-yl)pyrrolo[3,2-b]pyridin-6-yl]-3,5-dimethyl-isoxazole4-[1-[dideuterio-(4,4-difluorocyclohexyl)methyl]-3-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]pyrrolo[3,2-b]pyridin-6-yl]-3,5-dimethyl-isoxazole4-[1-[dideuterio-(4,4-difluorocyclohexyl)methyl]-3-(1,5-dimethylpyrazol-4-yl)pyrrolo[3,2-b]pyridin-6-yl]-3,5-dimethyl-isoxazole3-[4-[1-[dideuterio-(4,4-difluorocyclohexyl)methyl]-6-(3,5-dimethylisoxazol-4-yl)pyrrolo[3,2-b]pyridin-3-yl]pyrazol-1-yl]propanenitrile4-[1-[dideuterio-(4,4-difluorocyclohexyl)methyl]-3-(3-pyridyl)pyrrolo[3,2-b]pyridin-6-yl]-3,5-dimethyl-isoxazole4-[3-(2-cyclopropyl-4-pyridyl)-1-[dideuterio-(4,4-difluorocyclohexyl)methyl]pyrrolo[3,2-b]pyridin-6-yl]-3,5-dimethyl-isoxazole5-[1-[dideuterio-(4,4-difluorocyclohexyl)methyl]-6-(3,5-dimethylisoxazol-4-yl)pyrrolo[3,2-b]pyridin-3-yl]pyridin-2-ol4-[1-[dideuterio-(4,4-difluorocyclohexyl)methyl]-3-(6-methoxy-3-pyridyl)pyrrolo[3,2-b]pyridin-6-yl]-3,5-dimethyl-isoxazole

The compounds in Table II are disclosed in WO 2014/145051, includingmethods of how to make these compounds, and the contents of WO2014/145051 are incorporated herein by reference in its entirety.

In some embodiments, the present disclosure provides a method oftreating a cancer as described herein in a subject in need thereof byadministering to the subject an effective amount of a compound or acomposition including any one or more compound(s) as described herein,in combination with one or more other therapies or medical procedureseffective in treating the cancer. Other therapies or medical proceduresinclude suitable anticancer therapy (e.g. drug therapy, vaccine therapy,gene therapy, photodynamic therapy) or medical procedure (e.g. surgery,radiation treatment, hyperthermia heating, bone marrow or stem celltransplant). In one embodiment, the one or more suitable anticancertherapies or medical procedures is selected from treatment with achemotherapeutic agent (e.g. chemotherapeutic drug), radiation treatment(e.g. x-ray, γ-ray, or electron, proton, neutron, or α particle beam),hyperthermia heating (e.g. microwave, ultrasound, radiofrequencyablation), Vaccine therapy (e.g. AFP gene hepatocellular carcinomavaccine, AFP adenoviral vector vaccine, AG-858, allogeneicGM-CSF-secretion breast cancer vaccine, dendritic cell peptidevaccines), gene therapy (e.g. Ad5CMV-p53 vector, adenovector encodingMDA7, adenovirus 5-tumor necrosis factor alpha), photodynamic therapy(e.g. aminolevulinic acid, motexafin lutetium), oncolytic viral orbacterial therapy, surgery, or bone marrow and stem celltransplantation. In certain embodiments, the present disclosure providesa method of treating a cancer in a subject in need thereof byadministering to the subject an effective amount of a compound asdescribed herein and applying a radiation treatment as described hereineither separately or simultaneously. In one embodiment, the presentdisclosure provides a method for treating a cancer in a subject in needthereof by administering an effective amount of a compound as describedherein to the subject followed by a radiation treatment (e.g. x-ray,γ-ray, or electron, proton, neutron, or α particle beam). In anotherembodiment, the present disclosure provides a method for treating acancer in a subject in need thereof by applying a radiation treatment(e.g. x-ray, γ-ray, or electron, proton, neutron, or α particle beam) tothe subject followed by administering an effective amount of a compoundas described herein to the subject. In yet another embodiment, thepresent disclosure provides a method for treating a cancer in a subjectin need thereof by administering a compound as described herein and aradiation therapy (e.g. x-ray, γ-ray, or electron, proton, neutron, or αparticle beam) to the subject simultaneously.

In another aspect, the present disclosure provides kits or containersthat include a compound of Formulae (I) or (II); or a pharmaceuticallyacceptable salt, a solvate, a tautomer, an isomer, or a deuteratedanalog of Formulae (I) or (II); or any of the compounds in Table I, orany of the pharmaceutical compositions thereof described herein. In someembodiments, the compound or composition is packaged, e.g., in a vial,bottle, flask, which may be further packaged, e.g., within a box,envelope, or bag; the compound or composition is approved by the U.S.Food and Drug Administration or similar regulatory agency foradministration to a mammal, e.g., a human; the compound or compositionis approved for administration to a mammal, e.g., a human, for abromodomain protein mediated disease or condition; the kit or containerdisclosed herein may include written instructions for use and/or otherindication that the compound or composition is suitable or approved foradministration to a mammal, e.g., a human, for a bromodomain-mediateddisease or condition; and the compound or composition may be packaged inunit dose or single dose form, e.g., single dose pills, capsules, or thelike.

VII. Examples

The following examples are offered to illustrate, but not to limit thepresent disclosure.

Compounds within the scope of this disclosure can be synthesized asdescribed below, using a variety of reactions known to the skilledartisan. One skilled in the art will also recognize that alternativemethods may be employed to synthesize the target compounds of thepresent disclosure, and that the approaches described within the body ofthis document are not exhaustive, but do provide broadly applicable andpractical routes to compounds of interest. In some examples, the massspectrometry result indicated for a compound may have more than onevalue due to the isotope distribution of an atom in the molecule, suchas a compound having a bromo or chloro substituent.

Those skilled in the art will also recognize that during standard workup procedures in organic chemistry, acids and bases are frequently used.Salts of the parent compounds are sometimes produced, if they possessthe necessary intrinsic acidity or basicity, during the experimentalprocedures described within this patent.

Example 1A

Step 1: Preparation of tert-butyl6-(3,5-dimethylisoxazol-4-yl)-3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(2)

To a mixture of4-(3-iodo-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole (1, 25.3g, 74.6 mmol) and DMAP (455 mg, 3.73 mmol) in tetrahydrofuran (250 mL)was added dropwise a solution of di-tert-butyl carbonate (19.54 g, 89.52mmol) in tetrahydrofuran (50 mL). The reaction mixture was stirred atroom temperature for 30 minutes and concentrated under reduced pressure.The crude material was purified by column chromatography on silica gel(0-30% ethyl acetate in hexane). The fractions containing product werecombined, concentrated under reduced pressure, and dried under highvacuum overnight to provide tert-butyl6-(3,5-dimethylisoxazol-4-yl)-3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(2). MS (ESI) [M+H⁺]⁺=440.1.

Step 2: Preparation of tert-butyl6-(3,5-dimethylisoxazol-4-yl)-3-(4-(methoxycarbonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(3)

To a pressure vessel charged with tert-butyl6-(3,5-dimethylisoxazol-4-yl)-3-iodo-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(2, 15.0 g, 34.15 mmol) and (4-methoxycarbonylphenyl)boronic acid (12.3g, 68.32 mmol) in toluene (230 mL) and ethanol (70 mL) was added a 2 Maqueous solution of Na₂CO₃ (51 mL, 102.5 mmol) followed by addition of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.25 g, 1.7mmol). The resulting mixture was allowed stir under nitrogen for 5minutes. The vessel was then sealed and heated at 105-110° C. for 2.5hours. After completion, the reaction mixture was cooled down to roomtemperature, diluted with dichloromethane (300 mL), and filtered througha pad of celite. The solvents were concentrated under reduced pressureand the residue was poured into a saturated aqueous solution of NaHCO₃(300 mL) and extracted with ethyl acetate (2×200 mL). The combinedorganic layers were washed with water (2×200 mL) and brine (200 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was triturated with EtOAc/Et₂O/hexane and the resulting solidwas collected by filtration. The solid was washed with the mixture ofEtOAc/Et₂O and then dried under high vacuum to provide tert-butyl6-(3,5-dimethylisoxazol-4-yl)-3-(4-(methoxycarbonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(3). MS (ESI) [M+H⁺]⁺=447.48.

Step 3: Preparation of methyl4-(6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)benzoatehydrochloride (4)

To tert-butyl6-(3,5-dimethylisoxazol-4-yl)-3-(4-(methoxycarbonyl)phenyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(3, 39.5 g, 88.3 mmol) in CH₂Cl₂/MeOH (2:1, 350 mL) was added 4 M HCl indioxane (220 mL, 88 mmol) at 0° C., and the mixture was allowed to stirat ambient temperature for 2 days. The solid was collected byfiltration, washed with cold dichloromethane (150 mL) and withdiethylether (3×100 mL), and then dried under high vacuum to providemethyl4-(6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)benzoatehydrochloride (4). MS (ESI) [M+H⁺]⁺=347.12.

Step 4: Preparation of methyl4-(1-(di(pyridin-2-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)benzoate(5)

To methyl4-[6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl]benzoatehydrochloride (4, 1.33 g, 3.47 mmol) in THF (20 mL) was added cesiumcarbonate (3.39 g, 10.4 mmol) and 2-[bromo(2-pyridyl)methyl]pyridine(1.04 g, 4.16 mmol). The mixture was heated and allowed to stir at 70°C. for 24 hours. LC-MS showed that the starting material (methyl4-(6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)benzoate)was still present. Then, additional 2-[bromo(2-pyridyl)methyl]pyridine(500 mg, 2.01 mmol) was added into the reaction mixture and allowed tostir at 70° C. for another 24 hours. The reaction mixture was pouredinto water and extracted with ethyl acetate. The organic layer waswashed with water and brine, dried over MgSO₄, and filtered. Thevolatiles were removed under vacuum to provide crude material that waspurified by silica gel column chromatography (0-80% ethyl acetate indichloromethane). The fractions containing product were combined andconcentrated under reduced pressure and dried under high vacuumovernight to provide methyl4-(1-(di(pyridin-2-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)benzoate(5). MS (ESI) [M+H⁺]⁺=515.56.

Step 5: Preparation of methyl4-(1-(1,1-di(pyridin-2-yl)ethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)benzoate(P-002)

To methyl4-[1-[bis(2-pyridyl)methyl]-6-(3,5-dimethylisoxazol-4-yl)pyrrolo[3,2-b]pyridin-3-yl]benzoate(5, 0.36 g, 0.7 mmol) in tetrahydrofuran (15 mL) was added sodiumhydride (60% in mineral oil, 0.03 g, 0.8 mmol). The mixture was allowedto stir at room temperature for 10 minutes. Then, iodomethane (0.5 g,3.5 mmol) was added and the reaction mixture was allowed to stir at roomtemperature for 20 hours. The reaction mixture was poured into water andextracted with ethyl acetate. The organic layer was washed with waterand brine, dried over MgSO₄, and filtered. The volatiles were removedunder vacuum. The crude product was purified by silica gel columnchromatography (0-100% ethyl acetate in dichloromethane) The fractionscontaining product were combined and concentrated under reduced pressureand dried under high vacuum overnight to provide methyl4-(1-(1,1-di(pyridin-2-yl)ethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)benzoate(P-002). MS (ESI) [M+H⁺]⁺=529.59.

Step 6: Preparation of4-(1-(1,1-di(pyridin-2-yl)ethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)benzoicacid (P-001)

To methyl4-[1-[1,1-bis(2-pyridyl)ethyl]-6-(3,5-dimethylisoxazol-4-yl)pyrrolo[3,2-b]pyridin-3-yl]benzoate(P-002, 180 mg, 0.34 mmol) in THF (15 mL) was added 1 M lithiumhydroxide (7.5 mL) in water. The reaction mixture was heated and allowedto stir at 50° C. for 20 hours. The reaction mixture was poured intowater along with 5 mL of acetic acid and extracted with ethyl acetate.The organic layer was washed with water and brine, dried over MgSO4, andfiltered. After the volatiles were removed, the residue was dissolved inacetonitrile after heating to reflux. After cooling to room temperaturethe solution was allowed to sit in the refrigerator overnight. Theproduct was collected by filtration to provide4-(1-(1,1-di(pyridin-2-yl)ethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)benzoicacid (P-001). MS (ESI) [M+H⁺]⁺=515.56.

Alternatively, P-001 can be synthesized according to Example 1B:

Step 1: 3,5-Dimethyl-4-(1H-pyrrolo[3,2-b]pyridin-6-yl)isoxazole (8)

To a suspension of 6 (purchased from Synnovator, Inc.) (196.5 g, 0.997mol, 1 equiv), 7 (purchased from Oakwood Products, Inc.) (183 g, 1.296mol, 1.3 equiv), potassium carbonate (413 g, 2.992 mol, 3 equiv) andbis(triphenylphosphine)palladium(II) dichloride (34.9 g, 49.9 mmol, 114mmol, 0.05 equiv) in dioxane (2.8 L) and water (852 mL) was sparged withnitrogen for 10 minutes. The reaction mixture was heated at 90° C.overnight, at which point LC/MS indicated the reaction was complete. Thereaction was diluted with ethyl acetate (4 L) and water (4 L). Thelayers were separated and the organic layer was passed through silicagel (0.5 kg) rinsing with additional ethyl acetate (2 L). The filtratewas concentrated under reduced pressure and the crude residue wastriturated with MTBE (˜2 L) to give compound 3.

Step 2: 4-(3-Iodo-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole(2)

N-Iodosuccinimide (198 g, 882 mmol, 1.1 equiv) was added to a solutionof compound 3 (171 g, 802 mmol, 1 equiv) in a mixture of acetonitrile(7.3 L) and dimethylacetamide (730 mL). The reaction was stirredovernight at room temperature, at which point LC/MS indicated thereaction was complete. The acetonitrile was removed under reducedpressure and the residue was slurried in a mixture of warm water (8 L)and saturated sodium thiosulfate (2 L). The solid was collected byfiltration and washed with additional water (2 L). The crude solid wastriturated with MTBE (˜2 L) and to give 2 after drying in a convectionoven at 50° C. for two days.

Step 3: Di(pyridin-2-yl)methanol (10)

Sodium borohydride (27.1 g, 716 mmol, 0.38 equiv) was added in portionsto a solution of 9 (purchased from RennoteTech Co., LTD) (350. g, 1900mmol, 1 equiv) in methanol (7 L) at 0° C. The reaction was allowed tostir for 1.5 hours at which point LCMS indicated full consumption of 9.The solution was concentrated under reduced pressure. The residue wasdissolved in 1N hydrochloric acid (2.56 L). The pH was adjusted to ˜8with solid sodium bicarbonate (344 g). The solution was extracted twicewith ethyl acetate (2×3 L). The combined organic layers wereconcentrated under reduced pressure to give 10 which was usedsubsequently in the next step.

Step 4: 2,2′-(Bromomethylene)dipyridine dihydrobromic acid (11)

Triphenylphosphine dibromide (322.5 g, 764 mmol, 2 equiv) was added inportions to a solution of 9 (71.2 g, 382 mmol, 1 equiv) indichloromethane (1.6 L) at room temperature. The reaction was allowed tostir at room temperature overnight. The suspension was filtered undernitrogen and washed with dichloromethane (2×100 mL). The solid was driedunder vacuum oven at 40° C. for 3 hours to give 11. The solid washygroscopic and was not left exposed to air.

Step 5:4-(1-(Di(pyridin-2-yl)methyl)-3-iodo-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole(12)

11 (178.4 g, 435 mmol, 1.58 equiv) was suspended in a saturated solutionof sodium bicarbonate (2 L) and extracted with dichloromethane (3×1 L).The combined organic layers were concentrated under reduced pressure togive the free base of 11 (108.2 g, 435 mmol, 1.58 equiv). Free base of11 (108.2 g, 435 mmol, 1.58 equiv), 2 (93.5 g, 276 mmol, 1 equiv) andcesium carbonate (208 g, 638 mmol, 2.3 equiv) were dissolved in THF (3L) and refluxed overnight. The solution was diluted with saturated brine(3 L). The organic layer was separated and concentrated under reducedpressure. The residue was purified twice over silica gel (2×700 g),eluting each time with a gradient of 0 to 100% ethyl acetate indichloromethane. The material was triturated with MTBE (500 mL) to 12.

Step 6:4-(1-(1,1-Di(pyridin-2-yl)ethyl)-3-iodo-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole(13)

Potassium tert-butoxide (29.4 g, 239 mmol, 1.2 equiv) was added inportions to a solution of 12 (101.0 g, 199 mmol, 1 equiv) andiodomethane (37.2 mL, 597 mmol, 3 equiv) in anhydrous THF. The reactionwas allowed to stir at room temperature overnight. The solution wasquenched with saturated brine (2 L). The organic layer was separated andconcentrated under reduced pressure. The residue was partially purifiedover silica gel (1 kg) eluting with a gradient of 0 to 40% ethyl acetatein dichloromethane. The mixed fractions were purified in two batches onthe same AnaLogix column (220 g) eluting each time with 0 to 50% ethylacetate in dichloromethane Clean fractions were combined to give 13.

Step 7: Methyl4-(1-(1,1-di(pyridin-2-yl)ethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)benzoate(P-002)

A mixture of 13 (73.4 g, 141 mmol, 1 equiv), and 13b (purchased fromAngene International Limited) (50.7 g, 282 mmol, 2 equiv), and potassiumcarbonate (58.3 g, 422 mmol, 3 equiv) in dioxane (730 mL) and water (245mL) were sparged with nitrogen for 10 minutes.[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6.2 g, 8.4mmol, 0.06 equiv) was added and the reaction was heated to 80° C. for1.5 hours. After cooling to room temperature, the solution was dilutedwith THF (500 mL) and filtered through Celite (95 g), washing withadditional THF (600 mL). The Celite pad was slurried in dichloromethane(1 L) and filtered. The two filtrates were combined and concentratedunder reduced pressure. The residue was purified over silica gel (1 kg),eluting with a gradient of 0 to 100% ethyl acetate in heptanes. Themixed fractions were combined and triturated with MTBE (200 mL). Thefiltrate was concentrated under reduced pressure and purified on anAnaLogix column (220 g), eluting with a gradient of 0 to 50% ethylacetate in heptanes. All clean material was combined to give P-002.

Step 8:4-(1-(1,1-Di(pyridin-2-yl)ethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)benzoicacid (P-001)

A solution of P-002 (79.2 g, 150 mmol, 1 equiv) and 2M lithium hydroxide(1.125 L, 2250 mmol, 15 equiv) in THF (2.2 L) were heated to 55° C.overnight. The solution was diluted with saturated brine (2 L). The pHwas adjusted to ˜5 with 1 N hydrochloric acid (1.6 L). The solution wasextracted with ethyl acetate (2.2 L). The organic layer was separated,dried over sodium sulfate, and concentrated under reduced pressure. Theresidue was dissolved in dichloromethane (1 L) and filtered to removeinsoluble particles. The filtrate was diluted with acetonitrile (1 L)and concentrated to a thick slurry. The suspension was filtered. Thefiltrate was treated repeatedly in the same fashion until no isolablematerial remained. All solids were combined to give P-001.

Example 2

Step 1—Preparation of methyl4-(6-(3,5-dimethylisoxazol-4-yl)-1-(fluorodi(pyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)benzoate(P-003) and4-(6-(3,5-dimethylisoxazol-4-yl)-1-(fluorodi(pyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)benzoicacid (P-004)

In a vial charged with methyl4-[1-[bis(2-pyridyl)methyl]-6-(3,5-dimethylisoxazol-4-yl)pyrrolo[3,2-b]pyridin-3-yl]benzoate(5, 0.09 g, 0.17 mmol) and potassium hydroxide (150 mg, 2.68 mmol) wasadded N,N-dimethylformamide (2 mL). The mixture was allowed to stir atroom temperature for 1 hour and a solution of N-fluorobenzenesulfonimide(100 mg, 0.315.34 mmol) in 1 mL N,N-dimethylformamide was added. Themixture was allowed to stir at room temperature for 2 hours. Thereaction mixture was poured into water along with 5 mL of acetic acid,and then extracted with ethyl acetate. The organic layer was washed withwater and brine, dried over MgSO₄, and filtered. The crude product waspurified by preparative HPLC. The pure fractions were combined and driedon the lyophilizer to provide methyl4-(6-(3,5-dimethylisoxazol-4-yl)-1-(fluorodi(pyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)benzoate(P-003, 6 mg, 7%), MS (ESI) [M+H⁺]⁺=533.55; and4-(6-(3,5-dimethylisoxazol-4-yl)-1-(fluorodi(pyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)benzoicacid (P-004), MS (ESI) [M+H⁺]⁺=519.52.

Example 3

Step 1—Preparation of methyl4-[1-[cyano-bis(2-pyridyl)methyl]-6-(3,5-dimethylisoxazol-4-yl)pyrrolo[3,2-b]pyridin-3-yl]benzoate(P-005)

To a vial charged with methyl4-[1-[bis(2-pyridyl)methyl]-6-(3,5-dimethylisoxazol-4-yl)pyrrolo[3,2-b]pyridin-3-yl]benzoate(5, 0.08 g, 0.16 mmol) and potassium hydroxide (0.15 g, 2.67 mmol) wasadded N,N-dimethylformamide (5 mL) and the mixture was allowed to stirat room temperature for 10 minutes. Then, a solution of phenyl cyanate(20%, 0.4 g, 0.67 mmol) in dichloromethane was added to the reaction andallowed to stir at room temperature for 1 hour. LC-MS showed thereaction was not completed, so additional phenyl cyanate (20%, 0.3 gram,0.502 mmol) was added. The reaction mixture was allowed to stir at roomtemperature for another 2 hours. The reaction mixture was poured intowater along with 5 mL of acetic acid and extracted with ethyl acetate.The organic layer was washed with water and brine, dried over MgSO₄, andfiltered. The crude material was purified by silica gel columnchromatography (0-80% ethyl acetate in hexane). The fractions containingproduct were combined and concentrated under reduced pressure and driedunder high vacuum overnight to provide methyl4-[1-[cyano-bis(2-pyridyl)methyl]-6-(3,5-dimethylisoxazol-4-yl)pyrrolo[3,2-b]pyridin-3-yl]benzoate(P-005). MS (ESI) [M+H⁺]⁺=540.57.

Step 2—Preparation of4-[1-[cyano-bis(2-pyridyl)methyl]-6-(3,5-dimethylisoxazol-4-yl)pyrrolo[3,2-b]pyridin-3-yl]benzoicacid (P-006)

The product (P-006,4-[1-[cyano-bis(2-pyridyl)methyl]-6-(3,5-dimethylisoxazol-4-yl)pyrrolo[3,2-b]pyridin-3-yl]benzoicacid) was prepared as depicted in Step 6 of Example 1 using theappropriate starting materials. MS (ESI) [M+H⁺]⁺=526.54.

Another embodiment of this disclosure relates to a compound useful for asynthesis of the compound of claim 1, having one of the followingformulae:

or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer,or a deuterated analog thereof.

Example 4 Comparison of Rat PK Between Compound P-001 and Compound Z

Rat PK data was determined using a cassette dosing format with 5compounds administered to each of three rats for IV and three rats forPO. The IV dose was 1 mg/kg for each compound in 8.75% solutol, 8.75%ethanol, 12.5% DMSO and 70% water by volume. The PO dose was 2 mg/kg foreach compound in 1% methylcellulose in water, 10% DMSO by volume. PlasmaIV samples were collected at 15 min, 30 min, 1 hr, 2 hrs, 4 hrs, 8 hrs,and 24 hrs. Plasma PO samples were collected at 30 min, 1 hr, 2 hrs, 4hrs, 8 hrs, and 24 hrs. Plasma drug concentrations were determined byLC/MS/MS after standard curve calibration for each test article. Dosingsolutions were also analyzed for test article and used to calculate theadministered dose. The PK parameters were calculated using WinNonLin (v6.3, Phoenix 64, Pharsight) using a noncompartmental model.

Tables 1 and 2 show comparative data for both intravenous (IV) andperoral (PO) administration in rat for Compound P-001 of this disclosureand a similar structural compound disclosed in the WO 2014/145051,Compound Z. Values are reported as the Mean with the Standard Error (SE)in parentheses. The data demonstate a dramatic improvement in rat PK forCompound P-001 when compared to the rat PK for Compound Z.

TABLE 1 Intravenous (IV) Administration in Rat Dose AUC Compound (mg/kg)T_(1/2) (hr) T_(max) (hr) C_(max) (ng/mL) (hr * ng/mL)

  Compound Z 1.56 1.31 (0.15) 0.5 (0)  80 (11) 125 (15)

  Compound P-001 1.27 4.13 (0.74) 0.67 (0.17) 1212 (118)  7670 (451)

TABLE 2 Peroral (PO) Administration in Rat AUC Cl Compound (hr * ng/mL)Vss (L/Kg) (mL/min/Kg) % F

  Compound Z 125 (15) 1.061 (0.109) 36 (4)  17

  Compound P-001 7670 (451) 0.469 (0.015)  3 (0) 103

Example 5 Efficacy Comparison Between Compound P-001 and Compound ZUsing IPC298 Xenograft Model

Treatment: The treatments started on Day 11 after tumor inoculation whenthe mean tumor size reached approximately 150 mm³. Mice were randomizedinto 10 study groups and each group consisted of 8 mice. The testarticles were administrated to the tumor-bearing mice according topredetermined treatment regimen as shown in Table 3.

TABLE 3 Treatment Schedule Dosage** Group n* Treatment (mg/kg)Route/schedule 1 10 Vehicle control — po, QD × 16 2 8 Compound P-001 10po, QD × 16 3 8 Compound Z 10 po, QD × 16 Note: *= n equals the numberof animals **= Dosing volume: adjust dosing volume based on mouse bodyweight (5 μL/g).

Tumor measurements and the endpoints: The major endpoint was to see ifthe tumor growth could be delayed or regressed. Tumor size was measuredtwice a week in two dimensions using a caliper, and the volume wasexpressed in mm³ using the formula: V=0.5 a×b² where a and b are thelong and short diameters of the tumor, respectively. The tumor size wasthen used for calculation of tumor growth inhibition (TGI, in percent).The TGI value is an indication of antitumor effectiveness:TGI=(1−T/C)×100%. T and C are the means of relative tumor volumes of thetreated and control groups, respectively. T and C are calculated usingthe formula: T=T_(d)/T₀×100%, C=C_(d)/C₀×100%, where T_(d) and C_(d) aretumor volumes of the treated and control animals, respectively, on Day28 after tumor inoculation; T₀ and C₀ are tumor volumes of the treatedand control animals, respectively, at the start of the treatment

The tumor volumes in different groups at different time points are shownin Table 4 and Table 5 and FIG. 1. Compound P-001 alone demonstrated astrong antitumor activity with a mean tumor size of 99.2 mm³ (Table 4)and TGI=112% (Table 5) while Compound Z produced a moderate antitumoractivity with the mean tumor sizes were 141.5 mm³ (Table 4) and TGI=92%(Table 5).

TABLE 4 Average Tumor Volume (mm³) Group Day 0 Day 4 Day 6 Day 8 Day 11Day 13 Vehicle 124.3 173.7 214.8 240.6 282.3 336.5 Compound Z 124.0119.8 124.0 120.6 106.8 141.5 Compound 124.7 94.5 91.5 90.0 96.9 99.2P-001

TABLE 5 Tumor Size Group Treatment (Day 27, mm³⁾ TGI (%) 1 VehicleControl 336.5 ± 48.4 — 2 Compound Z (10 mg/kg) 141.5 ± 16.3  92 3Compound P-001 (10 mg/kg)  99.2 ± 13.5 112

Thus, Compound Z produced moderate antitumor activity, while CompoundP-001 demonstrated strong therapeutic efficacy. Test articles weretolerated well by the tumor-bearing animals.

Example 5 Toxicity Profile Comparison Between Compound P-001 andCompound Z

The promonocytic cell line, Ba/F3, depends on the addition of IL-3 forgrowth in cell culture. However Ba/F3 cells engineered to express a fulllength oncogene is capable of rendering Ba/F3 cells factor-independent,but become apoptotic when the oncogene or downstream signaling isinhibited by the addition of small molecule inhibitors. When injectedinto the tail veins of nude mice, the factor-independent Ba/F3 cellshome to the spleen and proliferate to cause a marked splenomegaly. Thein vivo proliferation of the factor-independent Ba/F3 cells andappearance of splenomegaly are directly dependent on the activity of theBa/F3 cells and can be blocked by oral administration of compounds thatare effective inhibitors of cell growth. Therefore, this animal modelcan be used to ascertain the effective doses for Ba/F3 cell inhibition,evaluation of both PK/PD effects as well as a readout of toxicity orMTD.

Table 6 provides a summary of the experimental design.

TABLE 6 DAY Ba/F3 cells scaled up in culture (six T-150's) 1 Cellswashed and prepared for injections at 5 × 10⁷ cells/mL 2 Inject tailveins of 24 mice (Groups 2-7), 0.1 mL (5 × 10⁶ cells) per mouse. Noinjection for Group 1 (Naive). 2-8 Wait 6 days while spleens are growing8 Treat vehicle and Compound Z or Compound P-001 by oral gavage. Groups2-7 QD. 15  Administer last dose and collect blood for PK analysisaccording to PK section below. 15  Weigh animals. Sac mice. Measurespleen and liver weights.

FIG. 2 illustrates the observed toxicity when dosing Compound P-001 andCompound Z at 10 mg/kg to nu/nu mice over a period of 7 days. Table 7contains delta body weight changes during period of dosing.

TABLE 7 Delta Body Weight Loss Compound Day 1 Day 2 Day 3 Day 5 Day 6Day 7 Compound Z 0 −0.125 −0.6 −1.125 −2.475 −3.75 10 mg/kg Compound 00.75 1.375 1.125 1.825 2.075 P-001 10 mg/kg

Thus, Compound P-001 shows a significantly improved toxicity profilethan Compound Z. As can be seen above, no toxicity was observed forCompound P-001 over the duration of dosing tested in this pharmacologymodel. Compound Z shows significant toxicity after the 2^(11d) day ofdosing, and mice continue to deteriorate for remainder of study.

Example 6 Compound Properties

While the inhibitory activity of the compounds on any bromodomain andmutants thereof is important to their activity in treating of disease,the compounds described herein show favorable properties that provideadvantages as a pharmaceutical as well.

The compounds described herein are useful for treating disorders relatedto bromodomain proteins and mutants thereof.

Alphascreen Binding Assay

Binding of compounds of Formula (I) with bromodomain 2, 3, and 4 wasassessed using Alphascreen binding assay. The inhibition of theinteraction between bromodomain and its acetylated target protein(Filippakopoulos P et al. 2012) was measured quantitatively usingrecombinant BRD proteins, an acetylated Histone 4 peptide andAlphaScreen™ technology. In absence of inhibition the BRD protein boundto AlphaScreen™ nickel chelate acceptor beads can interact with theacetylated Histone 4 peptide which is immobilized by the AlphaScreen™Streptavidin coated beads. This interaction brings donor and acceptorbeads in proximity. The close proximity allows the singlet oxygenproduced by laser excitation of the donor beads to reach the acceptorbeads and generate a luminescence signal. BRD inhibitors result in adecrease in the proximity signal through an inhibition of theBRD—acetylated peptide interaction.

Recombinant human bromodomains containing the N-terminal bromodomain(BRD2-BD1 (71-194), BRD3-BD1 (24-144) and BRD4-BD1 (44-164)) or dualbromodomains (BRD4-BD12 (1-477), BRD4-BD12 (1-472)) were prepared andpurified as described in protein expression and purification session.The peptide is human Histone H4₁₋₂₁K5_(Ac)K8_(Ac)K12_(Ac)K16_(Ac)-Biotin(Anaspec CA, USA).

Protocol for BRD2, BRD3 and BRD4 assay: All components are prepared inbuffer composed of 50 mM HEPES pH 7.5, 100 mM NaCl, 0.01% BSA, 0.01%Triton X-100, 2 mM DTT. 7 μL of Bromodomain protein and 7 μL of peptideare added to wells containing 14 of various concentrations of testcompounds of Formula (I) or DMSO vehicle in an Alphaplate (PerkinElmerGA, USA) and incubated for 1 hour at room temperature. 4 μL donor andacceptor bead mixture is then added with final concentrations of 7.5μg/mL. 30 minutes after bead addition, Alpha signal is read on theEnvision spectrometer (λ_(Ex) 680 nm, λ_(Em) 520-620 nm). Finalconcentrations of bromodomain proteins and peptide are as shown below.

Assay name BRD protein (nM) Peptide (nM) BRD2-BD1 6 41 BRD3-BD1 4 41BRD4-BD1 6 41 BRD2-BD12 1 10 BRD4-BD12 3.7 37

All data was normalized to the mean of 16 high and 16 low control wellson each plate. A four parameter curve fit of the following formula wasthen applied:Y=a+(b−a)/(1+(x/c)^d)Where ‘a’ is the minimum, ‘b’ is the maximum, ‘c’ is the pIC₅₀ and ‘d’is the Hill slope.Protein Expression and Purification

Recombinant human bromodomains containing the N-terminal bromodomain(BRD2-BD1 (71-194), BRD3-BD1 (24-144) and BRD4-BD1 (44-164)) or dualbromodomains (BRD4-BD12 (1-477), BRD4-BD12 (1-472)) were expressed in E.coli cells (in a modified pET vector) with an N-terminal six-His tag andpurified using a combination of both IMAC (Ni-affinity) and sizeexclusion chromatography steps.

Recombinant BRD proteins were expressed using the E. coli strainBL21-CodonPlus (DE3) (Agilent Technologies CA, USA). Cells were grown inTerrific Broth (TB) media to an OD600 of 1.2 at 37° C. at whichtemperature was reduced to 25° C., protein was induced with 1.0 mMispropyl-B-D-thiogalactopyranoside (“IPTG”) for 12-18 hours andharvested by centrifugation at 8000×g for 20 minutes. Cells werere-suspended in 0.1 M K₂PO₄ pH 8.0, 250 mM NaCl, 10% Glycerol, 0.75%NP-40, 25 mM Imidazole, 5 mM beta-mercaptoethanol (“BME”) with 0.2 mg/mLLysosyme, 2.0 mM phenylmethanesulfonyl fluoride (“PMSF”), 25 μg/mL DNAseI, incubated on ice for 30 minutes and lyzed with a cell disruptor(MicroFluidics MA, USA). The lysate was clarified by centrifugation at20,000×g for 2 hours. The protein was captured with Ni-NTA resin (LifeTechnologies, USA). Contaminating proteins were washed off with 25 mMTris-HCl pH 8.3, 250 mM NaCl, 12% Glycerol and 50 mM Imidazole.Following 3× wash steps, protein was eluted step wise using a 50 mMHEPES pH 7.5, 500 mM NaCl and 400 mM Imidazole. The protein was furtherpurified using Gel Filtration column 26/600 Superdex 200 (GE BiosciencesNJ, USA) in 50 mM HEPES pH 7.5, 250 mM NaCl. The protein was aliquotedand flash-frozen in liquid Nitrogen.

Oncology Cell Growth Assay

Published bromodomain inhibitors JQ1 and iBET 151 have shown activity invariety of cancer cells such leukemia and lymphoma, multiple myelomacells, NUT midline carcinoma and glioblastoma cells (Dawson M A et al.2011; Delmore J E 2011; Chen Z et al. 2013; Filippakopoulos P et al.2010; Mertz J A et al. 2011; Ott C J et al. 2012). In this study, wetest compounds in different cancer cell lines. MV-4-11 and MOLM-13 areAML cell lines harboring a MLL-AF4 and MLL-AF9 translocation,respectively. MM.1S is a multiple myeloma cell line. SK-N-AS, IMR-32 andSK-N-BE(2) are neuroblastoma cell lines. IMR-32 and SK-N-BE(2) celllines harbor MYCN amplifications.

MV-4-11, MM.1S, IMR-32, SK-N-AS and SK-N-BE(2) were obtained from ATCC(IL, USA) and MOLM-13 were purchased from DSMZ(Braunschweig, German).Cells are cultured as recommended by their sources. For growthinhibition studies 3000 cells are seeded in wells of a 96-well plate in75 μL of culture media. After several hours, growth media containingcompounds of Formula (I) are added to the wells. Compound at a maximalconcentration of 5 mM was serially diluted 1:3 for a total of 8 pointtitration with DMSO as a control. A 1 μL aliquot of each dilution pointis added to 249 μL growth media and 75 μL is added to each wellcontaining cells, providing 10 μM compound at the maximum concentrationpoint. The final concentration of DMSO in all wells is 0.2%. Cells areincubated for 72 hours, and 25 μL of CellTiter Glo Reagent (Promega GA,USA) is added to each well. Plates are shaken for approximately 10minutes and chemiluminescent signal is read on Tecan microplate reader.The measured luminescence correlates directly with cell number.

All data is normalized to the mean of eight DMSO high control wells oneach plate. A four parameter curve fit of the following formula was thenapplied:Y=a+(b−a)/(1+(x/c)^d)Where ‘a’ is the minimum, ‘b’ is the maximum, ‘c’ is the pIC50 and ‘d’is the Hill slope. These data demonstrate that the bromodomaininhibitors tested in the above assays inhibit cell growth in oncologycell lines.Myc Reporter Assay

In MV-4-11 cells, BRD2, BRD3 and BRD4 bind to the promoter region of MYCand regulate its transcription (Dawson M A et al. 2011). The literaturebromodomain inhibitor iBET 151 could disrupt BRD4 recruitment to the MYCpromoter and subsequently downregulate c-myc transcription (Dawson M Aet al. 2011). Myc protein is a transcription factor that heterodimerizeswith an obligatory partner Max and regulates the transcription of genesimportant for cell proliferation, differentiation, and apoptosis. ThisMyc reporter assay is used to monitor the inhibitory effect of compoundof Formula (I) on Myc dependent gene expression. Effective compoundscould have potential therapeutic effects in Myc-driven tumors.

The MV-4-11 Myc reporter cell line is established by infecting MV-4-11with VSV-g pseudotyped lentivirus expressing the firefly luciferase geneunder the control of a minimal (m) CMV promoter and tandem repeats ofthe E-box tranonriptional response element (TRE) (Qiagen IL, USA) andselecting cells in 2.5 μg/mL Puromycin.

The MV-4-11 Myc reporter cell line is maintained in Iscove's ModifiedDulbecco's Medium containing 10% FBS, 1% PenStep and 2.5 μg/mLPuromycin. Cells are incubated at 37° C. in a humidified atmosphere with5% CO₂. 25,000 cells are seeded in 96-well plate in 50 μL of culturemedia. After several hours, growth media containing 2× compounds areadded to the wells. Compound at a maximal concentration of 5 mM isserially diluted 1:3 for a total of 8 point titration. A 1 μL aliquot ofeach dilution point is added to 249 μL growth media and 50 μL is addedto each well containing cells, providing 10 μM compound at the maximumconcentration point. DMSO treated cells serve as a high control and 10μM JQ1 treated cells serve as a low control. Cells are incubated for afurther 24 hours and 25 μL of CellTiter-Fluo Reagent (Promega GA, USA)is added to each well. Plates are shaken for approximately 2 minutes andincubated at 37° C. for 0.5 hour. Fluorescence signal is read in a TecanPlate reader (λex=400 nm, λem=505 nm). 25 μL of One-Glo Reagent (PromegaGA, USA) is then added to the plates. Chemiluminescent signal is read onTecan plate reader. Values from the wells with no cells are subtractedfrom all samples for background correction. The background correctedfluorescence correlates directly with cell number, and luminescencecorrelates directly with Myc reporter activity.

All data is normalized to the mean of 8 high control and 4 low controlwells on each plate. A four parameter curve fit of the following formulawas then applied:Y=a+(b−a)/(1+(x/c)^d)Where ‘a’ is the minimum, ‘b’ is the maximum, ‘c’ is the pIC₅₀ and ‘d’is the Hill slope.

It is understood that the results of these assays may vary as assayconditions are varied. Inhibition levels determined under the conditionsdescribed herein represent a relative activity for the compounds testedunder the specific conditions employed. The cell based assays are likelyto show variability due to the complexity of the system and thesensitivity thereof to any changes in the assay conditions. As such,some level of inhibition in the cell based assays is indicative of thecompounds having some inhibitory activity for those cells, whereas lackof inhibition below the threshold of the highest concentration testeddoes not necessarily indicate that the compound has no inhibitoryactivity on the cells, only that under the conditions tested, noinhibition is observed. In some instances, the compounds were not testedin all of the assays, or assay results were not valid.

All patents, patent applications and other references cited in thespecification are indicative of the level of skill of those skilled inthe art to which the present disclosure pertains, and are incorporatedby reference in their entireties, including any tables and figures, tothe same extent as if each reference had been incorporated by referencein its entirety individually. The information provided is intendedsolely to assist the understanding of the reader. None of theinformation provided nor references cited is admitted to be prior art tothe present disclosure. Each of the references cited is incorporatedherein in its entirety and for any purpose.

One skilled in the art would readily appreciate that the presentdisclosure is well adapted to obtain the ends and advantages mentioned,as well as those inherent therein. The methods, variances, andcompositions described herein as presently representative of preferredembodiments are exemplary and are not intended as limitations on thescope of the present disclosure. Changes therein and other uses willoccur to those skilled in the art, which are encompassed within thespirit of the present disclosure, are defined by the scope of theclaims.

While this disclosure has been made with reference to specificembodiments, it is apparent that other embodiments and variations of thepresent disclosure may be devised by others skilled in the art withoutdeparting from the true spirit and scope of the present disclosure.

In addition, where features or aspects of the present disclosure aredescribed in terms of Markush groups or other grouping of alternatives,those skilled in the art will recognize that the present disclosure isalso thereby described in terms of any individual member or subgroup ofmembers of the Markush group or other group.

Also, unless indicated to the contrary, where various numerical valuesare provided for embodiments, additional embodiments are described bytaking any two different values as the endpoints of a range. Such rangesare also within the scope of the present disclosure.

What is claimed is:
 1. A compound of Formula (I):

or a pharmaceutically acceptable salt, a tautomer, a stereoisomer or adeuterated analog thereof, wherein: R¹ is cyano, halo, or (C₁-C₃)alkyloptionally substituted with 1 to 3 substituents independently selectedfrom the group consisting of halo, methyl, ethyl, methoxy and ethoxy;and X, when present, is halo.
 2. The compound of claim 1, wherein R¹ is(C₁-C₂)alkyl, cyano or fluoro.
 3. The compound of claim 2, wherein R¹ ismethyl.
 4. The compound of claim 2, wherein R¹ is fluoro.
 5. Thecompound of claim 2, wherein R¹ is cyano.
 6. A compound of Formula (II):

or a pharmaceutically acceptable salt, a tautomer, a stereoisomer, or adeuterated analog thereof, wherein: R¹ is (C₁-C₃)alkyl optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of halo, methyl, ethyl, methoxy and ethoxy.
 7. Thecompound of claim 6, wherein R¹ is methyl.
 8. A compound of formula:

or a pharmaceutically acceptable salt, a tautomer, or a deuteratedanalog thereof.
 9. A pharmaceutical composition comprising a compound ofclaim 6 and a pharmaceutical acceptable excipient or carrier.
 10. Apharmaceutical composition comprising a compound of claim 6 and anothertherapeutic agent.
 11. The pharmaceutical composition according to claim10, wherein the another therapeutic agent is i) an alkylating agentselected from adozelesin, altretamine, bizelesin, busulfan, carboplatin,carboquone, carmustine, chlorambucil, cisplatin, cyclophosphamide,dacarbazine, estramustine, fotemustine, hepsulfam, ifosfamide,improsulfan, irofulven, lomustine, mechlorethamine, melphalan,oxaliplatin, piposulfan, semustine, streptozocin, temozolomide,thiotepa, and treosulfan; ii) an antibiotic selected from bleomycin,dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin,menogaril, mitomycin, mitoxantrone, neocarzinostatin, pentostatin, andplicamycin; iii) an antimetabolite selected from the group consisting ofazacitidine, capecitabine, cladribine, clofarabine, cytarabine,decitabine, floxuridine, fludarabine, 5-fluorouracil, ftorafur,gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine,pemetrexed, raltitrexed, thioguanine, and trimetrexate; iv) an antibodytherapy agent selected from alemtuzumab, bevacizumab, cetuximab,galiximab, gemtuzumab, nivolumab, panitumumab, pembrolizumab,pertuzumab, rituximab, tositumomab, trastuzumab, and 90 Y ibritumomabtiuxetan; v) a hormone or hormone antagonist selected from the groupconsisting of anastrozole, androgens, buserelin, diethylstilbestrol,exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole,leuprolide, magestrol, raloxifene, tamoxifen, and toremifene; vi) ataxane selected from DJ-927, docetaxel, TPI 287, paclitaxel andDHA-paclitaxel; vii) a retinoid selected from alitretinoin, bexarotene,fenretinide, isotretinoin, and tretinoin; viii) an alkaloid selectedfrom etoposide, homoharringtonine, teniposide, vinblastine, vincristine,vindesine, and vinorelbine; ix) an antiangiogenic agent selected fromAE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenalidomide,and thalidomide; x) a topoisomerase inhibitor selected from amsacrine,edotecarin, exatecan, irinotecan, SN-38(7-ethyl-10-hydroxy-camptothecin), rubitecan, topotecan, and9-aminocamptothecin; xi) a kinase inhibitor selected from erlotinib,gefitinib, flavopiridol, imatinib mesylate, lapatinib, sorafenib,sunitinib malate, AEE-788, AG-013736, AMG 706, AMN107, BMS-354825,BMS-599626, UCN-01 (7-hydroxystaurosporine), vemurafenib, dabrafenib,trametinib, cobimetinib selumetinib and vatalanib; xii) a targetedsignal transduction inhibitor selected from bortezomib, geldanamycin,and rapamycin; xiii) a biological response modifier selected fromimiquimod, interferon-α and interleukin-2; xiv) an IDO inhibitor; andxv) a chemotherapeutic agent selected from 3-AP(3-amino-2-carboxyaldehyde thiosemicarbazone), altrasentan,aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide,elesclomol, eribulin mesylate (E7389), ixabepilone, lonidamine,masoprocol, mitoguanazone, oblimersen, sulindac, testolactone,tiazofurin, a mTOR inhibitor, a PI3K inhibitor, a Cdk4 inhibitor, an Aktinhibitor, a Hsp90 inhibitor, a farnesyltransferase inhibitor or anaromatase inhibitor (anastrozole letrozole exemestane); xvi) a Mekinhibitor; xvii) a tyrosine kinase inhibitor; xviii) a c-Kit mutantinhibitor, xix) an EGFR inhibitor, or xx) an epigenetic modulator. 12.The pharmaceutical composition according to claim 11, wherein theanother therapeutic agent is an epigenetic modulator selected from thegroup consisting of: (a) a DNA methyltransferase; (b) a histone orprotein methyltransferase; (c) a histone demethylase; (d) a histonedeacetylase inhibitor; (e) histone acetyltransferase; and (f) otherchromatin remodelers.
 13. The pharmaceutical composition according toclaim 12, wherein the epigenetic modulator is a histone deacetylaseinhibitor selected from the group consisting of: vorinostat, romidepsin,chidamide, panobinostat, belinostat, valproic acid, mocetinostat,abexinostat, entinostat, resminostat, givinostat, and quisinostat.
 14. Amethod for treating a subject suffering from or at risk of a disease orcondition mediated by a bromodomain, said method comprisingadministering to the subject in need thereof an effective amount of acompound of claim 6, wherein the disease or condition is an autoimmunecondition, an inflammatory condition or a combination thereof.
 15. Amethod for treating a subject suffering from or at risk of a disease orcondition mediated by a bromodomain, said method comprisingadministering to the subject in need thereof an effective amount of acompound of claim 6, wherein the disease or condition is selected fromthe group consisting of lung cancer, breast cancer, colon cancer,midline carcinomas, acral lentiginous melanoma, acute eosinophilicleukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acutemegakaryoblastic leukemia, acute monocytic leukemia, acute promyelocyticleukemia, adenocarcinoma, adult T-cell leukemia/lymphoma, aggressiveNK-cell leukemia, AIDS-related lymphoma, anaplastic large cell lymphoma,angioimmunoblastic T-cell lymphoma, B-cell chronic lymphocytic leukemia,B-cell prolymphocytic leukemia, B-cell lymphoma, bone cancer, Burkitt'slymphoma, cutaneous T-cell lymphoma, colorectal cancer, diffuse largeB-cell lymphoma, enteropathy-associated T-cell lymphoma, follicularlymphoma, glioblastoma multiforme, glioma, gastric cancer, hepatosplenicT-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, leukemia,lymphoma, acute lymphocytic leukemia, acute myelogenous leukemia,chronic lymphocytic leukemia, small cell lung cancer, non-small celllung cancer, MALT lymphoma, malignant peripheral nerve sheath tumor,mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia,medullary carcinoma of the breast, medulloblastoma, melanoma, merkelcell cancer, mesothelioma, multiple myeloma, neuroblastoma,neurofibroma, nodular melanoma, osteosarcoma, ovarian cancer, precursorT-lymphoblastic lymphoma, primary central nervous system lymphoma,primary effusion lymphoma, prostate cancer, pancreatic cancer, skincancer, T cell lymphoma, and uveal melanoma.
 16. The method of claim 14,wherein the autoimmune condition or inflammatory condition is selectedfrom the group consisting of, ulcerative colitis, chronic obstructivepulmonary disease (COPD), atherosclerosis, rheumatoid arthritis,psoriatic arthritis, juvenile arthritis, and osteoarthritis.
 17. Themethod of claim 14, wherein the autoimmune condition or inflammatorycondition is selected from the group consisting of rheumatoid arthritis,osteoarthritis, ulcerative colitis, and atherosclerosis.
 18. A methodfor treating a subject suffering from or at risk of a disease orcondition mediated by a bromodomain, said method comprisingadministering to the subject in need thereof an effective amount of acompound of claim 6, wherein the disease or condition is non-small celllung cancer, small cell lung cancer, ovarian cancer, melanoma, midlinecarcinomas, breast cancer, lymphomas, neuroblastoma, castrationresistant prostate cancer, myelofibrosis, myelodysplastic syndromes, oracute myeloid leukemia.
 19. The method of claim 15, further comprisingadministering quizartinib to said subject.
 20. A compound useful for asynthesis of the compound of claim 1, having one of the followingformulae:

or a pharmaceutically acceptable salt, a tautomer or a deuterated analogthereof.